KR20120089437A - Flavin derivatives - Google Patents

Abstract

The present invention relates to the use and compositions for use as novel flavin derivatives and other flavin derivatives, riboswitch ligands and / or anti-infective agents. The invention also relates to a process for the preparation of the novel flavin derivatives.

Description

Flavin derivatives {FLAVIN DERIVATIVES}

This application claims priority to US Provisional Application No. 61 / 221,937, filed June 30, 2009, and US Provisional Application No. 61 / 303,237, filed February 10, 2010, the contents of which are incorporated by reference in their entirety. Incorporated herein by reference.

The present invention relates to flavin derivatives and compositions and uses for use as riboswith ligands and / or anti-infectives. The invention also relates to a process for the preparation of the novel flavin derivatives.

The rapid increase in antibiotic resistance over the past decades has raised serious concern that currently available antibiotic treatment options will soon be ineffective. Antibiotics are commonly used, and in contrast to the older chemical scaffolds that can be used for treatment, the rate of increase in bacterial resistance is so fast that it is urgent to develop new drugs in the fight against bacterial pathogens.

In many bacteria and fungi, RNA structures called riboswitches regulate the expression of various genes that are important for survival or toxicity. Each known class of riboswitch members can be folded into characteristic three-dimensional structural receptors that are typically located in the 5'-untranslated region (5'-UTR) of a particular mRNA to recognize a particular organic metabolite. If cognate metabolites are present at sufficiently high concentrations during transcription of the mRNA, riboswitch receptors change the gene expression by inducing structural changes in the generator mRNA that bind to the metabolite and prevent the expression of the open reading frame (ORF). In the absence of cognate metabolites, riboswitches are folded into structures that do not interfere with the expression of the ORF.

Sixteen different classes of riboswitches have been reported. Riboswitch members of each class bind to the same metabolite and share a highly conserved sequence and secondary structure. Riboswitch motifs include thiamine pyrophosphate (TPP), flavin mononucleotide (FMN), glycine, guanine, 3'-5'-cyclic diguanylic acid (c-di-GMP), molybdenum cofactor, glucoseamine-6- It has been shown to bind to phosphate (GlcN6P), lysine, adenine and adocobalamin (AdoCbl) riboswitches. In addition, four characteristic riboswitch motifs have been identified that recognize S-adenosylmethionine (SAM) I, II and III, IV, and two characteristic motifs recognize pre-keosin-1 (PreQ1). It was confirmed. Some antimetabolic ligands also bind to pyrithiamine pyrophosphate (PTPP), L-aminoethylcysteine (AEC), and DL-4-oxarisine and FMN riboswitch, which bind to lysine riboswitch, which binds to TPP riboswitch. It has been shown to bind to known ribosewitch classes, including ioflavin and FMN. Riboswitch-receptors bind to each ligand at the interface approaching the level of complexity and selectivity of the protein. This highly specific interaction can identify riboswitches for closely related ligand analogs. For example, guanine-binding riboswitch receptors derived from Bacillus subtilis form a three-dimensional structure so that the ligand is most fully accepted. Guanine is located between two aromatic bases and each polar functional group of guanine hydrogen binds to four additional riboswitch nucleotides surrounding it. This level of selectivity allows the identification of riboswitches for the most closely related purine analogs. Similarly, studies of SAM-binding riboswitches have shown that almost all functional groups of SAM are important for ligand binding, such as S-adenosyl homocysteine (SAH) and S-adenosylmethionine (SAM), where only one methyl group differs. Similar compounds can be identified. Similarly, TPP riboswitch is not a thiazole moiety but a negatively charged fatigue of ligand and one subdomain that recognizes all polar functional groups of the 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP) moiety. Some water molecules that bind to the phosphate moiety and other subdomains that coordinate the two metal ions. Similar to TPP, guanine and SAM riboswitches, FMN riboswitches form highly specific receptor structures for the natural metabolite FMN. This is due to a very specific interaction that allows the design of small molecules for the regulation of specific genes.

The riboswitches are particularly important in the present invention because FMN riboswitches bind to flavin mononucleotides (FMNs) and inhibit the expression of enzymes involved in riboflavin and FMN biosynthesis. Riboflavin is a water-soluble vitamin that is converted by flavokinase and FAD synthase into FMN and FAD cofactors, which are essential cofactors involved in energy metabolism and metabolism of fats, ketones, carbohydrates and proteins, which are important for all organisms. Vertebrates rely on the absorption of vitamins from the digestive tract for riboflavin sources, but most prokaryotes, fungi and plants synthesize riboflavin necessary for survival. Thus, it is suggested that compounds selective for FMN riboswitches may be useful targets for bacterial pathogens by stopping the biosynthesis of riboflavin, which is important for survival or toxicity. It has also been found that no examples of FMN, TPP, or any other riboswitch class exist in humans at present. Thus, riboswitches seem to offer the potential for the discovery of selective antigenic drugs. In addition, mr. CD3299 riboswitch found in C. difficile bacteria is important in the present invention. Therefore, it is an object of the present invention to provide a method for treating infection comprising administering novel flavin derivatives and / or flavin derivatives that target FMN and / or CD3299 riboswitches and / or are active against various bacterial colonies. It is.

Summary of the Invention

In a first embodiment, the invention relates to compounds of formula Q, in free or salt form:

<Formula Q>

In the above formulas,

(i) Alk is C _1-6 alkylene (eg, methylene, ethylene, n-propylene, n-butylene or n-pentylene);

(ii) X is -N (R ₆ ) and A is

-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),

-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, (isoxazol-5-yl) methyl, tetrazolyl, Pyridyls such as pyrid-3-yl, (pyrid-5-yl) methyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl) [wherein the above-alkylaryl ¹ and -alkylhetero aryl alkyl groups of ^1-hydroxy-1, or another aryl group (e.g., phenyl) optionally are substituted, wherein - the ^first and alkyl aryl-alkyl-aryl group and heteroaryl ^{1 1 1} of heteroaryl one or more

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

          -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );

-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;

-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);

-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);

-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);

-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);

-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);

-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);

-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;

-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl; or

Para-phenylbenzyl; or

X is a single bond and A is monocyclic heteroaryl ² (eg pyrrolyl, eg pyrrole-1-yl; pyridyl, eg pyrid-2-yl, pyrid-4-yl or pyrid) -3-yl; tetrazolyl, eg 1,2,3,4-tetrazol-1-yl; imidazolyl, eg imidazol-1-yl; or isoxazolyl, eg isoxazole -5-yl), wherein the monocyclic heteroaryl ² is optionally substituted with C _1-4 alkyl (eg methyl); or

X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH _2- , -N (R ₆ ) -CH ₂ CH _2- , -N (R ₆ ) -C (H) (CH ₃ )-or -C (O)-, and

A is C _3-8 cycloalkyl ² (eg, C ₄ cycloalkyl ² or C _5-6 cycloalkyl ² ), wherein at least one carbon atom of said cycloalkyl ² is N, O, S, S (O) ₂ or Optionally and independently substituted with -C (O)-, for example

           Cyclobutyl,

           Cyclopentyl,

           Cyclohexyl,

           1-methylcyclohex-1-yl,

           Piperidinyl (eg, piperidin-1-yl),

           Pyrrolidinyl (e.g., pyrrolidin-1-yl),

           Morpholinyl (eg, morpholin-4-yl),

           Azapanyl (eg, azapan-1-yl),

           Piperazinyl,

           2,5-dioxopiperazin-1-yl,

           Tetrahydropyranyl (eg, tetrahydropyran-4-yl),

           Isoxazolidinyl (isoxazolidin-5-yl),

           1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl,

           1,1,3-trioxo-1,2,5-thiazolidin-2-yl,

           2-oxocyclopentylideneyl,

           2-oxooxazolidin-5-yl,

           2-oxopyrimidin-1-yl or

           2,4-dioxo-imidazolidin-3-yl,

Wherein said cycloalkyl ² is at least one

C _1-4 alkyl (eg methyl),

-C (O) OR ₇ ,

-CH ₂ C (O) OR ₇ ,

-N (R ₆ ) C (O) OR ₇ ,

          -OH,

Hydroxy-C _1-4 alkyl (eg hydroxymethyl),

C _1-4 alkoxy (eg methoxy),

-CH ₂ N (R ₆ ) -C (O) OR ₇ ,

² aryl (e.g., phenyl) or aryl ² -C _{1 -4} alkyl (e.g., benzyl) wherein the aryl ² or aryl ^2, wherein the ^second group of the alkyl aryl C _{1 - 4} alkyl optionally substituted with (e. G., Methyl) ], For example 4-methylphenyl, 2-methylphenyl,

Heteroaryl ² (eg 2H-tetrazol-5-yl),

Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl),

-C _1-4 alkyl-N (R ₈ ) (R ₉ ) (eg -methyl-NH ₂ -or -ethyl-NH ₂ ),

C _1-4 alkoxy (eg methoxy),

-C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H) S (O) ₂ -CH ₃ ),

-N (H) -S (O) ₂ -C _1-4 alkyl (e.g., -N (H) -S (O) ₂ -methyl),

-S (O) ₂ -N (R ₈ ) (R ₉ ) (e.g. -S (O) ₂ -NH ₂ ),

          -C (O) N (H) CN,

-C (O) N (R ₈ ) (R ₉ ) or

Optionally substituted with —N (R ₈ ) (R ₉ ); or

A is a 7-11 membered fused cycloalkyl-aryl or helical compound wherein at least one carbon atom can be a hetero atom selected from N, O or S, wherein the fused cycloalkyl-aryl or helical group is at least one hydroxy Optionally substituted with C _1-4 alkyl (eg methyl) or oxo (ie ═O)], for example

3,9-diazaspiro [5.5] undecane-3-yl,

3,9-diazaspiro [5.5] undecane-9-day,

(6-oxo-7-oxa-2-azaspiro [4.4] nonan-2-yl),

(9-oxo-8-oxa-3-azaspiro [4.4] nonan-3-yl),

(1-oxo-2,8-diazaspiro [4.5] decane-8-yl),

(2,4-dioxo-3,8-diazaspiro [4.5] decane-8-yl),

Indolinyl (e.g. indolin-1-yl),

Indanyl (eg, indan-1-yl, indan-2-yl or 2-hydroxyindan-1-yl),

Tetralinyl (e.g. tetralin-2-yl, tetralin-1-yl),

Isoindolinyl (e.g. isoindolin-2-yl),

Adamantyl,

3,4-dihydro-1H-isoquinolin-2-yl or 3,4-dihydro-2H-quinolin-1-yl,

1,3,4,5-tetrahydro-2-benzazin-2-yl,

2,3,4,5-tetrahydro-1-benzazin-1-yl,

1,2,4,5-tetrahydro-3-benzazin-3-yl;

(iii) R ₁ is H or C _1-8 alkyl (eg methyl);

(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl (eg -O- Cyclopentyl);

(v) R ₄ and R ₅ are

H,

C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),

-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],

Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,

Aryl ² -C _1-4 alkyl, wherein the aryl ² group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;

(vi) R ₆ is H or C _1-4 alkyl (eg methyl);

(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;

(viii) R ₈ and R ₉ are independently H or C _1-4 alkyl;

(ix) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );

(x) R ₁₁ and R ₁₂ are independently H or C _1-4 alkyl.

The present invention relates to compounds of hunger formula Q-I in free or salt form:

<Formula Q-I>

In the above formulas,

(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene, n-butylene or n-pentylene);

(ii) X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH _2- , -N (R ₆ ) -CH ₂ CH _2- , -N (R ₆ ) -C (H ) (CH ₃ )-or -C (O)-, and

A is —C _3-8 cycloalkyl ² (eg, C ₄ cycloalkyl ² or C _5-6 cycloalkyl ² ), wherein at least one carbon atom of said cycloalkyl ² is N, O, S, S (O) ₂ Or optionally and independently substituted with -C (O)-, for example

           Cyclobutyl,

           Cyclopentyl,

           Cyclohexyl,

           1-methylcyclohex-1-yl,

           Piperidinyl (eg, piperidin-1-yl),

           Pyrrolidinyl (e.g., pyrrolidin-1-yl),

           Morpholinyl (eg, morpholin-4-yl),

           Azapanyl (eg, azapan-1-yl),

           Piperazinyl,

           2,5-dioxopiperazin-1-yl,

           Tetrahydropyranyl (eg, tetrahydropyran-4-yl),

           Isoxazolidinyl (isoxazolidin-5-yl),

           1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl,

           1,1,3-trioxo-1,2,5-thiazolidin-2-yl,

           2-oxocyclopentylideneyl,

           2-oxooxazolidin-5-yl,

           2-oxopyrimidin-1-yl or

           2,4-dioxo-imidazolidin-3-yl);

Wherein said cycloalkyl ² is at least one

C _1-4 alkyl (eg methyl),

-C (O) OR ₇ ,

-CH ₂ C (O) OR ₇ ,

-N (R ₆ ) C (O) OR ₇ ,

          -OH,

Hydroxy-C _1-4 alkyl (eg hydroxymethyl),

C _1-4 alkoxy (eg methoxy),

-CH ₂ N (R ₆ ) -C (O) OR ₇ ,

² aryl (e.g., phenyl) or aryl ² -C _1-4 alkyl (e.g., benzyl) wherein the aryl ² or aryl ^2-aryl wherein the alkyl group is optionally substituted by ^two C _1-4 alkyl (e.g., methyl) ], For example 4-methylphenyl, 2-methylphenyl;

Heteroaryl ² (eg 2H-tetrazol-5-yl),

Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl),

-C _1-4 alkyl-N (R ₈ ) (R ₉ ) (eg -methyl-NH ₂ -or -ethyl-NH ₂ ),

C _1-4 alkoxy (eg methoxy),

-C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H) S (O) ₂ -CH ₃ ),

-N (H) -S (O) ₂ -C _1-4 alkyl (e.g., -N (H) -S (O) ₂ -methyl),

-S (O) ₂ -N (R ₈ ) (R ₉ ) (e.g. -S (O) ₂ -NH ₂ ),

         -C (O) N (H) CN,

-C (O) N (R ₈ ) (R ₉ ) or

Optionally substituted with —N (R ₈ ) (R ₉ ); or

A is a 7-11 membered fused cycloalkyl-aryl or helical compound wherein at least one carbon atom can be a hetero atom selected from N, O or S, wherein the fused cycloalkyl-aryl or helical group is at least one hydroxy Optionally substituted with C _1-4 alkyl (eg methyl) or oxo (ie ═O)], for example

3,9-diazaspiro [5.5] undecane-3-yl,

3,9-diazaspiro [5.5] undecane-9-day,

(6-oxo-7-oxa-2-azaspiro [4.4] nonan-2-yl),

(9-oxo-8-oxa-3-azaspiro [4.4] nonan-3-yl),

(1-oxo-2,8-diazaspiro [4.5] decane-8-yl),

(2,4-dioxo-3,8-diazaspiro [4.5] decane-8-yl),

Indolinyl (e.g. indolin-1-yl),

Indanyl (eg, indan-1-yl, indan-2-yl or 2-hydroxyindan-1-yl),

Tetralinyl (e.g. tetralin-2-yl, tetralin-1-yl),

Isoindolinyl (e.g. isoindolin-2-yl),

Adamantyl,

3,4-dihydro-1H-isoquinolin-2-yl or 3,4-dihydro-2H-quinolin-1-yl,

1,3,4,5-tetrahydro-2-benzazin-2-yl,

2,3,4,5-tetrahydro-1-benzazin-1-yl,

1,2,4,5-tetrahydro-3-benzazin-3-yl,

(ii) R ₁ is H or C _1-8 alkyl (eg methyl);

(iii) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl (eg -O- Cyclopentyl);

(v) R ₄ and R ₅ are

H,

C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),

-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],

Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,

Aryl ² -C _1-4 alkyl, wherein the aryl ² group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;

(vi) R ₆ is H or C _1-4 alkyl (eg methyl);

(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;

(viii) R ₈ and R ₉ are independently H or C _1-4 alkyl;

(ix) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ).

The present invention further relates to compounds of formula Q-II in free or salt form:

<Formula Q-II>

In the above formulas,

(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene, n-butylene or n-pentylene);

(ii) X is a single bond and A is monocyclic heteroaryl ² (eg pyrrolyl, eg pyrrole-1-yl; pyridyl, eg pyrid-2-yl, pyrid-4-yl Or pyrid-3-yl; tetrazolyl, eg 1,2,3,4-tetrazol-1-yl; imidazolyl, eg imidazol-1-yl; or isoxazolyl, eg g. isoxazol-5-yl), wherein said heteroaryl ² is one or more C _{1 - 4} and optionally substituted with alkyl (e.g., methyl);

(iii) R ₁ is H or C _1-8 alkyl (eg methyl);

(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl ² (eg -O -Cyclopentyl);

(v) R ₄ and R ₅ are

H,

C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),

-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],

Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,

Aryl ² -C _1-4 alkyl, wherein the aryl group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;

(vi) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;

(vii) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ).

The invention further relates to compounds of formula Q-III, which are in free or salt form:

<Formula Q-III>

In the above formulas,

(i) Alk is C _1-6 alkylene (eg, methylene, ethylene, n-propylene, n-butylene or n-pentylene);

(ii) X is -N (R ₆ ) and A is

-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),

-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, (isoxazol-5-yl) methyl, tetrazolyl, Pyridyls such as pyrid-3-yl, (pyrid-5-yl) methyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl) [wherein the above-alkylaryl ¹ and -alkylhetero aryl alkyl groups of ^1-hydroxy-1, or another aryl group (e.g., phenyl) optionally are substituted, wherein - the ^first and alkyl aryl-alkyl-aryl group and heteroaryl ^{1 1 1} of heteroaryl one or more

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

         -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );

-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;

-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);

-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);

-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);

-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);

-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);

-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);

-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;

-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl;

Para-phenylbenzyl;

(iii) R ₁ is H or C _1-8 alkyl (eg methyl);

(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl ² (eg -O -Cyclopentyl);

(v) R ₄ and R ₅ are

H,

C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),

-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],

Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,

Aryl ² -C _1-4 alkyl, wherein the aryl group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;

(vi) R ₆ is H or C _1-4 alkyl (eg methyl);

(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;

(viii) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );

(ix) R ₁₁ and R ₁₂ are independently H or C _1-4 alkyl.

The present invention relates to compounds of formula Q-IV in free or salt form:

<Formula Q-IV>

In the above formulas,

(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene);

(ii) X is a single bond and A is pyrrolyl such as pyrrole-1-yl or imidazolyl such as imidazol-1-yl; or

X is a single bond, and A is pyrrolidinyl (eg pyrrolidin-1-yl) or piperidi optionally substituted with another aryl (eg phenyl) or aryl-C _1-4 alkyl (eg benzyl) Nil (eg piperidin-1-yl); or

X is -N (R ₆ )-and A is tetralinyl (eg, tetralin-2-yl);

(iii) R ₁ is H or C _1-8 alkyl (eg methyl);

(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl);

(v) R ₆ is H or C _1-4 alkyl (eg methyl);

(vi) R ₁₀ is H.

The invention further relates to compounds of formula Q-V, which are in free or salt form:

<Formula Q-V>

In the above formulas,

(i) Alk is C _1-6 alkylene (eg methylene, ethylene or n-propylene);

(ii) X is a single bond and A is pyrrolyl optionally substituted with another aryl (e.g. phenyl) or aryl-C _1-4 alkyl (e.g. benzyl), e.g. pyrrole-1-yl, pyrroli Dinil (eg pyrrolidin-1-yl) or piperidinyl (eg piperidin-1-yl);

(iii) R ₁ is C _1-8 alkyl (eg methyl);

(iv) R ₂ is C _1-4 alkyl (eg methyl);

(v) R ₁₀ is H.

In a further embodiment of the first embodiment, the invention relates to compounds of formula Q or any Q-I to Q-V, which are in free or salt form as described by the following formula:

Q.1. Alk is a compound of Formula Q or any QI to QV wherein C _1-6 alkylene (eg methylene, ethylene or n-propylene);

Q.2. Alk is ethylene; or a compound of Formula Q or any QI to QV, Q.1;

Q.3. X is -N (R ₆ ) and A is

-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),

-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, (isoxazol-5-yl) methyl, tetrazolyl, Pyridyls such as pyrid-3-yl, (pyrid-5-yl) methyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl) [wherein the above-alkylaryl ¹ and -alkylhetero aryl alkyl groups of ^1-hydroxy-1, or another aryl group (e.g., phenyl) optionally are substituted, wherein - the ^first and alkyl aryl-alkyl-aryl group and heteroaryl ^{1 1 1} of heteroaryl one or more

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

        -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );

-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;

-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);

-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);

-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);

-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);

-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);

-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);

-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;

-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl; or

Para-phenylbenzyl; or

X is a single bond and A is monocyclic heteroaryl ² (eg pyrrolyl, eg pyrrole-1-yl; pyridyl, eg pyrid-2-yl, pyrid-4-yl or pyrid) -3-yl; tetrazolyl, eg 1,2,3,4-tetrazol-1-yl; imidazolyl, eg imidazol-1-yl; or isoxazolyl, eg isoxazole -5-yl), wherein the monocyclic heteroaryl ² is optionally substituted with C _1-4 alkyl (eg methyl); or

X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH _2- , -N (R ₆ ) -CH ₂ CH _2- , -N (R ₆ ) -C (H) (CH ₃ )-or -C (O)-, and

A is C _3-8 cycloalkyl ² (eg, C ₄ cycloalkyl ² or C _5-6 cycloalkyl ² ), wherein at least one carbon atom of said cycloalkyl ² is N, O, S, S (O) ₂ or Optionally and independently substituted with -C (O)-, for example

     Cyclobutyl,

     Cyclopentyl,

     Cyclohexyl,

     1-methylcyclohex-1-yl,

     Piperidinyl (eg, piperidin-1-yl),

     Pyrrolidinyl (e.g., pyrrolidin-1-yl),

     Morpholinyl (eg, morpholin-4-yl),

     Azapanyl (eg, azapan-1-yl),

     Piperazinyl

     2,5-dioxopiperazin-1-yl,

     Tetrahydropyranyl (eg, tetrahydropyran-4-yl),

     Isoxazolidinyl (isoxazolidin-5-yl),

     1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl,

     1,1,3-trioxo-1,2,5-thiazolidin-2-yl,

     2-oxocyclopentylideneyl,

     2-oxooxazolidin-5-yl,

     2-oxopyrimidin-1-yl or

     2,4-dioxo-imidazolidin-3-yl);

Wherein said cycloalkyl ² is at least one

C _1-4 alkyl (eg methyl),

-C (O) OR ₇ ,

-CH ₂ C (O) OR ₇ ,

-N (R ₆ ) C (O) OR ₇ ,

     -OH,

Hydroxy-C _1-4 alkyl (eg hydroxymethyl),

C _1-4 alkoxy (eg methoxy),

-CH ₂ N (R ₆ ) -C (O) OR ₇ ,

² aryl (e.g., phenyl) or aryl ² -C _1-4 alkyl (e.g., benzyl) wherein the aryl ² or aryl ^2-aryl wherein the alkyl group is optionally substituted by ^two C _1-4 alkyl (e.g., methyl) ], For example 4-methylphenyl, 2-methylphenyl),

Heteroaryl ² (eg 2H-tetrazol-5-yl),

Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl),

-C _1-4 alkyl-N (R ₈ ) (R ₉ ) (eg -methyl-NH ₂ -or -ethyl-NH ₂ ),

C _1-4 alkoxy (eg methoxy),

-C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H) S (O) ₂ -CH ₃ ),

-N (H) -S (O) ₂ -C _1-4 alkyl (e.g., -N (H) -S (O) ₂ -methyl),

-S (O) ₂ -N (R ₈ ) (R ₉ ) (e.g. -S (O) ₂ -NH ₂ ),

     -C (O) N (H) CN,

-C (O) N (R ₈ ) (R ₉ ) or

Optionally substituted with —N (R ₈ ) (R ₉ ); or

A is a 7-11 membered fused cycloalkyl-aryl or helical compound wherein at least one carbon atom can be a hetero atom selected from N, O or S, wherein the fused cycloalkyl-aryl or helical group is at least one hydroxy Optionally substituted with C _1-4 alkyl (eg methyl) or oxo (ie ═O)], for example

3,9-diazaspiro [5.5] undecane-3-yl,

3,9-diazaspiro [5.5] undecane-9-day,

(6-oxo-7-oxa-2-azaspiro [4.4] nonan-2-yl),

(9-oxo-8-oxa-3-azaspiro [4.4] nonan-3-yl),

(1-oxo-2,8-diazaspiro [4.5] decane-8-yl),

(2,4-dioxo-3,8-diazaspiro [4.5] decane-8-yl),

Indolinyl (e.g. indolin-1-yl),

Indanyl (eg, indan-1-yl, indan-2-yl or 2-hydroxyindan-1-yl),

Tetralinyl (e.g. tetralin-2-yl, tetralin-1-yl),

Isoindolinyl (e.g. isoindolin-2-yl),

Adamantyl,

3,4-dihydro-1H-isoquinolin-2-yl or 3,4-dihydro-2H-quinolin-1-yl,

1,3,4,5-tetrahydro-2-benzazin-2-yl,

2,3,4,5-tetrahydro-1-benzazin-1-yl,

A compound of Formula Q or any Q-I to Q-V, Q.1 or Q.2, which is 1,2,4,5-tetrahydro-3-benzazin-3-yl;

Q.4. X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH _2- , -N (R ₆ ) -CH ₂ CH _2- , -N (R ₆ ) -C (H) (CH ₃ )-or -C (O)-;

A is -C _{3 -8} ^{cycloalkyl. 2} (e, C ₄ cycloalkyl or ^two C _{5 - 6} cycloalkyl, ²⁾ wherein at least one carbon atom of the cycloalkyl is ² N, O, S, S ( O) 2 Or optionally and independently substituted with -C (O)-, for example

     Cyclobutyl,

     Cyclopentyl,

     Cyclohexyl,

     1-methylcyclohex-1-yl,

     Piperidinyl (eg, piperidin-1-yl),

     Pyrrolidinyl (e.g., pyrrolidin-1-yl),

     Morpholinyl (eg, morpholin-4-yl),

     Azapanyl (eg, azapan-1-yl),

     Piperazinyl,

     2,5-dioxopiperazin-1-yl,

     Tetrahydropyranyl (eg, tetrahydropyran-4-yl),

     Isoxazolidinyl (isoxazolidin-5-yl),

     1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl,

     1,1,3-trioxo-1,2,5-thiazolidin-2-yl,

     2-oxocyclopentylideneyl,

     2-oxooxazolidin-5-yl,

     2-oxopyrimidin-1-yl or

     2,4-dioxo-imidazolidin-3-yl);

Wherein said cycloalkyl ² is at least one

C _1-4 alkyl (eg methyl),

-C (O) OR ₇ ,

-CH ₂ C (O) OR ₇ ,

-N (R ₆ ) C (O) OR ₇ ,

        -OH,

Hydroxy-C _1-4 alkyl (eg hydroxymethyl),

C _1-4 alkoxy (eg methoxy),

-CH ₂ N (R ₆ ) -C (O) OR ₇ ,

² aryl (e.g., phenyl) or aryl ² -C _1-4 alkyl (e.g., benzyl) wherein the aryl ² or aryl ^2-aryl wherein the alkyl group is optionally substituted by ^two C _1-4 alkyl (e.g., methyl) ], For example 4-methylphenyl, 2-methylphenyl,

Heteroaryl ² (eg 2H-tetrazol-5-yl),

Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl),

-C _1-4 alkyl-N (R ₈ ) (R ₉ ) (eg -methyl-NH ₂ -or -ethyl-NH ₂ ),

C _1-4 alkoxy (eg methoxy),

-C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H) S (O) ₂ -CH ₃ ),

-N (H) -S (O) ₂ -C _1-4 alkyl (e.g., -N (H) -S (O) ₂ -methyl),

-S (O) ₂ -N (R ₈ ) (R ₉ ) (e.g. -S (O) ₂ -NH ₂ ),

        -C (O) N (H) CN,

-C (O) N (R ₈ ) (R ₉ ) or

Optionally substituted with —N (R ₈ ) (R ₉ ); or

A is a 7-11 membered fused cycloalkyl-aryl or helical compound wherein at least one carbon atom can be a hetero atom selected from N, O or S, wherein the fused cycloalkyl-aryl or helical group is at least one hydroxy Optionally substituted with C _1-4 alkyl (eg methyl) or oxo (ie ═O)], for example

3,9-diazaspiro [5.5] undecane-3-yl,

3,9-diazaspiro [5.5] undecane-9-day,

(6-oxo-7-oxa-2-azaspiro [4.4] nonan-2-yl),

(9-oxo-8-oxa-3-azaspiro [4.4] nonan-3-yl),

(1-oxo-2,8-diazaspiro [4.5] decane-8-yl),

(2,4-dioxo-3,8-diazaspiro [4.5] decane-8-yl),

Indolinyl (e.g. indolin-1-yl),

Indanyl (eg, indan-1-yl, indan-2-yl or 2-hydroxyindan-1-yl),

Tetralinyl (e.g. tetralin-2-yl, tetralin-1-yl),

Isoindolinyl (e.g. isoindolin-2-yl),

Adamantyl,

3,4-dihydro-1H-isoquinolin-2-yl or 3,4-dihydro-2H-quinolin-1-yl,

1,3,4,5-tetrahydro-2-benzazin-2-yl,

2,3,4,5-tetrahydro-1-benzazin-1-yl,

A compound of Formula Q, or any Q-I to Q-V, Q.1 or Q.2, which is 1,2,4,5-tetrahydro-3-benzazin-3-yl;

Q.5. X is a single bond and A is monocyclic heteroaryl ² (eg pyrrolyl, eg pyrrole-1-yl; pyridyl, eg pyrid-2-yl, pyrid-4-yl or pyrid) -3-yl; tetrazolyl, eg 1,2,3,4-tetrazol-1-yl; imidazolyl, eg imidazol-1-yl; or isoxazolyl, eg isoxazole -5-day);

Wherein said heteroaryl ² is one or more C _{1 - 4} alkyl (e.g., methyl) optionally substituted by the formula Q, or any QI to QV, compounds of Q.1 or Q.2;

Q.6 . X is -N (R ₆ ) and A is

-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),

-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, (isoxazol-5-yl) methyl, tetrazolyl, Pyridyls such as pyrid-3-yl, (pyrid-5-yl) methyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl), wherein the -alkylaryl ¹ and -alkylhetero aryl alkyl groups of ^1-hydroxy-1, or another aryl group (e.g., phenyl) optionally are substituted, wherein - the ^first and alkyl aryl-alkyl-aryl group and heteroaryl ^{1 1 1} of heteroaryl one or more

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

        -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );

-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;

-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);

-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);

-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);

-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);

-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);

-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);

-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;

-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl;

A compound of Formula Q or any QI to QV, Q.1 or Q.2 , which is para-phenylbenzyl;

Q.7. X is -N (R ₆ ) and A is

-C _1-4 alkyl-aryl ¹ (eg benzyl) or -C _1-4 alkyl-heteroaryl ¹ (eg isoxazol-5-yl) methyl, (pyrid-5-yl) methyl) [wherein -alkyl aryl ^first and -alkyl-alkyl-heteroaryl ¹ group is hydroxymethyl or another aryl ¹ (e. g., phenyl) optionally is substituted, the above-alkylaryl ^first and -alkyl-aryl-heteroaryl ¹ and heteroaryl ¹ group 1 Species or more

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

     -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

-SO ₂ -C _{1 - 4} alkyl (e.g., -SO ₂ -CH ₃₎ by the formula Q, or any QI to QV, compounds of Q.1 or Q.2 substituted independently;

Q.8. X is a single bond and A is pyrrolyl such as pyrrole-1-yl or imidazolyl such as imidazol-1-yl, or any QI to QV, Q.1 or Q.2 Compound of;

Q.9. X is a single bond, and A is pyrrolidinyl (eg pyrrolidin-1-yl) or piperidi optionally substituted with another aryl (eg phenyl) or aryl-C _1-4 alkyl (eg benzyl) A compound of Formula Q, or any QI to QV, Q.1 or Q.2, which is nil (eg, piperidin-1-yl);

Q.10. X is -N (R ₆ )-and A is tetralinyl (eg, tetralin-2-yl); or a compound of Formula Q. or any QI to QV, Q.1 or Q.2;

Q.11. R ₁ is C _{1 - 8} alkyl (e.g., methyl), the formula Q, or any QI to QV, or any compound of Q.1-Q.10;

Q.12. R ₁ is methyl; or a compound of Formula Q, or any QI to QV, or any Q.1-Q.10;

Q.13. R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl (eg -O-cyclopentyl) A compound of Formula Q, or any QI to QV, or any Q.1-Q.12;

Q.14. R ₂ is C _{1 - 4} alkyl (such as methyl) of the formula Q, or any QI to QV, or any compound of Q.1-Q.13;

Q.15. R ₂ is methyl or a compound of Formula Q or any QI to QV or any Q.1 - Q.14 ;

Q.16. R ₂ is a compound of Formula Q, or any QI to QV, or any Q.1-Q.13, wherein -N (R ₄ ) (R ₅ );

Q.17. R ₄ and R ₅

H,

C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),

-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ),

Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,

Aryl ² -C _1-4 alkyl, wherein the aryl ² group is optionally substituted with halo (eg fluoro); for example, formula Q.16 independently selected from 4-fluorophenylethyl;

Q.18. R ₆ is H or C _{1 - 4} alkyl (such as methyl) of the formula Q, or any QI to QV, or any compound of Q.1-Q.17;

Q.19. R ₆ is H, a compound of Formula Q, or any QI to QV, or any Q.1-Q.17;

Q.20. R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), a formula Q wherein -CH ₂ OC (O) CH ₃ , or any QI to QV, or any Q.1-Q .19 compound;

Q.21. R ₇ is H; a compound of Formula Q, or any QI to QV, or any Q.1-Q.20;

Q.22. R ₇ is C _{1 - 4} alkyl (e.g., methyl, ethyl or tert- butyl), the formula Q, or any QI to QV, or any compound of Q.1-Q.20;

Q.23. R ₇ is a compound of Formula Q, or any QI to QV, or any Q.1-Q.20, wherein -CH ₂ OC (O) CH ₃ ;

Q.24. R ₈ and R ₉ are independently H or C _{1 - 4} alkyl, the formula Q, or any QI to QV, or any compound of Q.1-Q.23;

Q.25. R ₈ and R ₉ are H, a compound of Formula Q, or any QI to QV, or any Q.1-Q.24;

Q.26. R ₈ and R ₉ is C _{1 - 4} alkyl, the formula Q, or any QI to QV, or any compound of Q.1-Q.24;

Q.27. R ₁₀ is H or -C _{1 - 4} alkyl, -OC (O) CH ₃ (for _{example, -CH 2 OC (O) CH} 3) of the formula Q, or any QI to QV, or any Q.1-Q A compound of .26;

Q.28. R ₁₀ is -C _{1 - 4} alkyl, -OC (O) CH ₃ (for _{example, -CH 2 OC (O) CH} 3) of the formula Q, or a compound of any of QI to QV, or any Q.1-Q .27 compound;

Q.29. R ₁₀ is H, or a compound of Formula Q, or any QI to QV, or any Q.1 - Q.27 ;

Q.30. R ₁₁ and R ₁₂ are independently H or C _{1 - 4} alkyl, the formula Q, or any QI to QV, or any compound of Q.1-Q.29;

Q.31. R ₁₁ is H, a compound of Formula Q, or any QI to QV, or any Q.1-Q.30;

Q.32. R ₁₁ is C _{1 - 4} alkyl, the formula Q, or any QI to QV, or any compound of Q.1-Q.30;

Q.33. R ₁₂ is H, a compound of Formula Q, or any QI to QV, or any Q.1-Q.32;

Q.34. R ₁₂ is C _{1 - 4} alkyl, the formula Q, or any QI to QV, or any compound of Q.1-Q.32;

Q.35. Any preceding formula wherein said compound is selected from:

Q.36. Any preceding formula wherein said compound is selected from:

Q.37. Any preceding formula wherein said compound is selected from:

Q.38. Any preceding formula wherein said compound is selected from:

Q.39. Any preceding formula wherein said compound is selected from:

Q.40. Any preceding formula wherein said compound is selected from:

Q.41. Any preceding formula wherein said compound is selected from:

Q.42. A compound of Formula Q, or any QI to QV, is bound to FMN and / or CD3299 riboswitch, for example, I _max is 20% relative to standard compound at 100 μM in an assay as described, for example, in Example 1 Greater than or, the IC ₅₀ value is 10 μM or less for the FMN riboswitch in the assay as described in Example 1, and / or the minimum inhibitory concentration (MIC) is for example in the assay as described in Example 2 Any preceding formula that is 128 μg / ml or less, preferably 64 μg / ml or less, more preferably 32 μg / ml or less.

In a particular embodiment of the first embodiment, the compound of formula Q, or any QI to QV, for example any Q.1 - Q.22 as described above, is

(a) when R ₂ is chloro, Alk is propylene, X is a single bond, and A is pyrrolidin-1-yl, then R ₁ is C _1-8 alkyl (e.g. methyl) or R ₁₀ is- C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ), ie the compound is 8-chloro-10- (3-pyrrolidin-1-ylpropyl) benzo [ g] not pteridine-2,4-dione;

(b) The compound is 10- [3- (3,6-dioxo-1,4-cyclohexadien-1-yl) propyl) -3,7,8-trimethyl-benzo [g] pteridine-2 , 4- (3H, 10H) -dione;

(c) A is not furinyl, for example the compound is optionally substituted 10- [2- (9H-purin-9-yl) ethyl]-, 10- [3- (9H-purin-9-yl) Propyl]-or 10- [6- (9H-purin-9-yl) hexyl] -7,8-dimethyl-benzo [g] pteridine-2,4- (3H, 10H) -dione;

(d) A is not indol-3-yl, for example the compound is 10- [3- (1H-indol-3-yl) ethyl]-or 10- [3- (1H-indol-3-yl) Propyl] -7,8-dimethyl-benzo [g] pteridine-2,4- (3H, 10H) -dione;

(e) Compounds Q, QI, Q-II, Q-III, Q-IV, which contain the proviso provision that -Alk-XA is not 2- (2-oxocyclopentylidene) ethyl, and which have the proviso provision QV refers to compounds of formula Q (i), QI (i), Q-II (i), Q-III (i), Q-IV (i), QV (i), respectively.

In a second embodiment, the invention relates to compounds of formula I (A) in free, salt or prodrug form:

<Formula I (A)>

In the above formulas,

(i) Alk is C _1-6 alkylene (eg methylene or ethylene);

(ii) X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH ₂ -or -C (O)-;

(iii) A is monocyclic heteroaryl ² (eg, pyrid-4-yl or pyrid-3-yl) or C _5-6 cycloalkyl ^2, wherein at least one carbon atom of said cycloalkyl ² is N, O Optionally and independently substituted with S or -C (O)-(eg piperidinyl (eg piperidin-1-yl), pyrrolidinyl (eg pyrrolidin-1-yl) , Piperazinyl (eg 2,5-dioxopiperazin-1-yl), isoxazolidinyl (isoxazolidin-5-yl), 1,1-dioxo-1,4-thiazinane- 4-yl, C _3-8 cycloalkyl ² (eg cyclopentyl, cyclohexyl or 2-oxocyclopentylidene), 2-oxopyrimidin-1-yl or 2,4-dioxo-imidazole- 3-yl) [wherein said heteroaryl ² and cycloalkyl ² are one or more -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ ,- OH, hydroxy-C _1-4 alkyl (eg hydroxymethyl), —CH ₂ N (R ₆ ) -C (O) OR ₇ , heteroaryl ² (eg 2H-tetrazol-5-yl), heteroaryl ² -C _1-4 alkyl (for example, 2H- tetrazol-5-yl-methyl), C _1-4 amines al (E. G., Amine-ethyl), C _1-4 alkoxy (e.g., methoxy), -C (O) N ( R 6) -S (O) 2 -C 1-4 alkyl (e.g., -C (O) Independently substituted with N (H) S (O) ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ );

(iv) R ₁ is H or C _1-8 alkyl (eg methyl);

(v) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), —N (R ₄ ) (R ₅ );

(vi) R ₄ and R ₅ are H, C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl), -C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is -OH,- C (O) OR ₇ , optionally substituted with one or more groups selected from aryl ² (eg, 4-fluorophenyl), optionally substituted with halo];

(vii) R ₆ is H or C _1-4 alkyl (eg methyl);

(viii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;

(ix) R ₈ and R ₉ are independently H or C _1-4 alkyl;

(x) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ).

The invention further relates to compounds of formula (A) as follows in free, salt or prodrug form:

1.1 Alk is C _{1 - 6} alkylene (e.g., ethylene) are compounds of formula I (A);

1.2 Alk is C _{1 - 2} alkylene (e.g., ethylene) are compounds of formula I (A), or 1.1;

1.3 a compound of Formula I (A) or 1.1 , wherein Alk is ethylene;

1.4 Alk is C _{3 - 6} alkylene group (for example, pentylene, and the like), a compound of formula I (A), or 1.1;

1.5 X is a single bond, a compound of Formula I (A) or any 1.1-1.4, wherein -N (R ₆ )-, -N (R ₆ ) -CH ₂ -or -C (O)-;

1.6 X is -N (R ₆ )-, or a compound of Formula I (A) or any 1.1-1.5;

1.7 A compound of Formula I (A) or any 1.1-1.5, wherein X is -N (R ₆ ) -CH _2- ;

1.8 X is a compound of Formula I (A) or any 1.1-1.5, wherein -C (O)-;

1.9 X is a compound of Formula I (A) or any 1.1-1.5 wherein it is a single bond;

1.10 A is a monocyclic heteroaryl ² (eg pyrid-4-yl or pyrid-3-yl) or C _5-6 cycloalkyl ² wherein at least one carbon atom of said cycloalkyl ² is N, O, S Optionally substituted with S (O) ₂ or -C (O)-(eg piperidinyl (eg piperidin-1-yl), pyrrolidinyl (eg pyrrolidin-1-yl) ), Piperazinyl (eg 2,5-dioxopiperazin-1-yl), isoxazolidinyl (isoxazolidin-5-yl), 1,1-dioxo-1,4-thiazinane 4-yl, C _3-8 cycloalkyl ² (eg cyclopentyl, cyclohexyl or 2-oxocyclopentylidene), 2-oxopyrimidin-1-yl or 2,4-dioxo-imidazole -3-yl) [wherein said heteroaryl ² and cycloalkyl ² are one or more -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (eg hydroxymethyl), -CH ₂ N (R ₆ ) -C (O) OR ₇ , heteroaryl ² (eg 2H-tetrazol-5-yl) , Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl), amine C _1-4 alkyl (eg amine -Ethyl), C _1-4 alkoxy (e.g. methoxy), -C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g. -C (O) N (H) Independently optionally substituted with S (O) ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ )] or a compound of Formula I (A) or any 1.1-1.9;

1.11 A is a compound of Formula I (A) or any 1.1-1.10, wherein monocyclic heteroaryl ² (eg, pyrid-4-yl or pyrid-3-yl);

1.12 A is C _5-6 cycloalkyl ^2, wherein at least one carbon atom of said cycloalkyl ² is optionally substituted with N, O, S, S (O) ₂ or —C (O) — (eg pipepe Ridinyl (eg piperidin-1-yl), pyrrolidinyl (eg pyrrolidin-1-yl), piperazinyl (eg 2,5-dioxopiperazin-1-yl), isocyanate Sazolidinyl (isoxazolidin-5-yl), 1,1-dioxo-1,4-thiazinan-4-yl, C _3-8 cycloalkyl ² (eg, cyclopentyl or cyclohexyl), 2 -Oxopyrimidin-1-yl or 2,4-dioxo-imidazol-3-yl), wherein the heteroaryl ² and cycloalkyl ² are one or more -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (eg hydroxymethyl), -CH ₂ N (R ₆ ) -C (O OR ₇ , heteroaryl ² (eg 2H-tetrazol-5-yl), heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl), amineC _1-4 alkyl (E.g. amine-ethyl), C _1-4 alkoxy (e.g. methoxy), -C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g. -C (O) N (H) S (O) ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ ) independently optionally substituted] or a compound of Formula I (A) or any 1.1-1.10;

1.13 A is optionally piperidinyl (eg piperidin-1-yl), pyrrolidinyl (eg pyrrolidin-1-yl), piperazinyl (eg 2,5-dioxopiperazin-1 -Yl), isoxazolidinyl (isoxazolidin-5-yl), 1,1-dioxo-1,4-thiazinan-4-yl, C _3-8 cycloalkyl ² (eg cyclopentyl or Cyclohexyl), 2-oxopyrimidin-1-yl or 2,4-dioxo-imidazol-3-yl), wherein said cycloalkyl ² is at least one -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (eg hydroxymethyl), -CH ₂ N (R ₆ ) -C ( O) OR ₇ , heteroaryl ² (eg 2H-tetrazol-5-yl), heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl), amine C _1-4 Alkyl (eg amine-ethyl), C _1-4 alkoxy (eg methoxy), -C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (eg -C (O) ) N (H) S (O) ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ ) optionally substituted] with compounds of Formula I (A) or any 1.1-1.10;

1.14 -Alk-XA is a compound of Formula I (A) or any 1.1-1.3 or 1.5-1.13 selected from any of the following;

1.15 -Alk-XA is a compound of Formula I (A) or any 1.1-1.3 or 1.5-1.13 selected from any of the following;

1.16 a compound of Formula I (A), 1.1 or any 1.4-1.6, 1.9-1.13, wherein -Alk-XA is selected from any of:

1.17 R ₁ is H or C _{1 - 8} alkyl (such as methyl) of the formula I (A) or compounds of any of 1.1 to 1.16;

1.18 Compound of Formula I (A) or any 1.1-1.16, wherein R ₁ is H;

1.19 R ₁ is C _{1 - 8} alkyl (such as methyl) of the formula I (A) or compounds of any of 1.1 to 1.16;

1.20 R ₂ is H, halo (e.g., chloro), C _{1 - 4} alkyl (e.g., _{methyl), -N (R 4) (} R 5) of the formula I (A) or compounds of any of 1.1 to 1.19;

1.21 A compound of Formula I (A) or any 1.1-1.19, wherein R ₂ is H;

1.22 A compound of Formula I (A) or any 1.1-1.19, wherein R ₂ is halo (eg, chloro);

1.23 R ₂ is C _{1 - 4} alkyl (such as methyl) of the formula I (A) or compounds of any of 1.1 to 1.19;

1.24 R ₂ is —N (R ₄ ) (R ₅ ), wherein R ₄ and R ₅ are H, C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl), —C _1-4 alkyl (eg , Methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ , aryl optionally substituted with halo (eg, 4-fluorophenyl) A compound of Formula (I) or any 1.1-1.19;

1.25 Formula 1.24, wherein R ₄ or R ₅ is H;

1.26 R ₄ or R ₅ is C _{3 -7} of Formula 1.24 or 1.25 ² cycloalkyl (e.g., cyclopropyl or cyclopentyl);

1.27 R ₄ or R ₅ is —C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is —OH, —C (O) OR ₇ , aryl optionally substituted with halo (eg 4-fluoro Formula 1.24 or 1.25, optionally substituted with one or more groups selected from phenyl);

1.28 R ₄ or R ₅ from any H, —C _1-4 alkyl (eg methyl or ethyl), cyclopentylamine, —CH ₂ CH ₂ -C (O) OC (CH ₃ ) ₃ or hydroxyethyl Formula 1.24 or 1.25 selected;

1.29 R ₆ is H or C _{1 - 4} alkyl (such as methyl) of the formula I (A) or compounds of any of 1.1 to 1.28;

1.30 R ₆ is H, or a compound of Formula 1.1 (A) or any 1.1-1.28;

1.31 R ₆ is C _{1 - 4} alkyl (such as methyl) of the formula (I) or compounds of any of 1.1 to 1.28;

1.32 R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), a compound of Formula I (A) or any 1.1-1.31 wherein —CH ₂ OC (O) CH ₃ ;

1.33 A compound of Formula I (A) or any 1.1-1.31, wherein R ₇ is H;

1.34 R ₇ is C _{1 - 4} alkyl (e.g., methyl, ethyl or tert- butyl), the formula I (A) or compounds of any of 1.1 to 1.31;

1.35 R ₇ is a compound of Formula I (A) or any 1.1-1.31, wherein -CH ₂ OC (O) CH ₃ ;

1.36 R ₁₀ is H or -C _{1 - 4} alkyl, -OC (O) CH ₃ (for _{example, CH 2 OC (O) CH} 3) of the formula I (A) or compounds of any of 1.1 to 1.35;

1.37 A compound of Formula I (A) or any 1.1-1.35, wherein R ₁₀ is H;

1.38 R ₁₀ is -C _{1 - 4} alkyl, -OC (O) CH ₃ (for _{example, CH 2 OC (O) CH} 3) of the formula I (A) or compounds of any of 1.1 to 1.35;

1.39 Any preceding formula wherein the compound of Formula I (A) is selected from any of the following:

1.40 Any preceding formula wherein the compound of Formula I (A) is selected from any of the following:

1.41 Any preceding formula wherein the compound of Formula I (A) is selected from any of:

1.42 Any preceding formula, wherein the compound of Formula I (A) is selected from:

;

;

1.43 A compound of Formula I (A) or any 1.1-1.38 selected from any of the following;

1.44 A compound of formula I (A) is bound to an FMN riboswitch, for example an IC ₅₀ of 100 μM or less, preferably less than 75 μM, more preferably 50 in an assay as described for example in Example 1 less than μM, still more preferably less than 25 μM, most preferably less than 10 μM and / or the minimum inhibitory concentration (MIC) is 128 μg / ml or less, preferably in an assay as described in Example 2, for example. Any preceding formula is less than 32 μg / ml.

In certain embodiments, any of 1.1 g of the compound as described, for example, of formula I (A) as described above - is 1.44 and R ₂ is chloro, and Alk is propylene, X is a single bond, A is pyrrolidine -1 When- ₁ , R ₁ is C _1-8 alkyl (eg methyl) or R ₁₀ is —C _1-4 alkyl-OC (O) CH ₃ (eg —CH ₂ OC (O) CH ₃ ), That is, the compounds of formula (A) include the proviso provisions other than 8-chloro-10- (3-pyrrolidin-1-ylpropyl) benzo [g] pteridine-2,4-dione (see above) Compounds with the provisions are compounds of Formula I (A) (i)).

In a third embodiment, the invention relates to compounds of formula II (A) in free, salt or prodrug form:

<Formula II (A)>

In the above formulas,

(i) Alk is C _1-6 alkylene (eg methylene, ethylene, pentylene);

(ii) Y is -N (R ₆ ) -C (O)-or -C (O) -N (R ₆ )-;

(iii) A is at least one -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (Eg hydroxymethyl), -CH ₂ N (R ₆ ) -C (O) OR ₇ , heteroaryl ² (eg 2H-tetrazol-5-yl), heteroaryl ² -C _1-4 alkyl ( Eg, 2H-tetrazol-5-yl-methyl), amine C _1-4 alkyl (eg amine-ethyl), C _1-4 alkoxy (eg methoxy), -C (O) N (R ₆ ) Heteroaryl optionally substituted with -S (O) ₂ -C _1-4 alkyl (eg, -C (O) N (H) S (O) ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ ) ² (eg, pyrid-3-yl);

(iv) R ₁ is H or C _1-8 alkyl (eg methyl);

(v) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), —N (R ₄ ) (R ₅ );

(vi) R ₄ and R ₅ are independently selected from H, C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl), —C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl Is optionally substituted with one or more groups selected from —OH, —C (O) OR ₇ , aryl (eg 4-fluorophenyl) optionally substituted with halo;

(vii) R ₆ is H or C _1-4 alkyl (eg methyl);

(viii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;

(ix) R ₈ and R ₉ are independently H, C _1-4 alkyl;

(x) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ).

In a particular embodiment of the third embodiment, the invention relates to compounds of formula II (A) as follows in free, salt or prodrug form:

2.1 a compound of Formula II (A) wherein Y is -N (R ₆ ) -C (O)-;

2.2 A compound of Formula II (A) wherein Y is -C (O) -N (R ₆ )-;

2.3 A is at least one -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (e.g. , Hydroxymethyl), -CH ₂ N (R ₆ ) -C (O) OR ₇ , heteroaryl ² (eg 2H-tetrazol-5-yl), heteroaryl ² -C _1-4 alkyl (eg, 2H-tetrazol-5-yl-methyl), amine C _1-4 alkyl (eg amine-ethyl), C _1-4 alkoxy (eg methoxy), -C (O) N (R ₆ ) -S (O) heteroaryl ² optionally substituted with ₂ -C _1-4 alkyl (eg, -C (O) N (H) S (O) ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ ) Eg, pyrid-3-yl), a compound of Formula II (A), 2.1 or 2.2;

2.4 A is at least one -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (e.g. , Hydroxymethyl), -CH ₂ N (R ₆ ) -C (O) OR ₇ , heteroaryl ² (eg 2H-tetrazol-5-yl), heteroaryl ² -C _1-4 alkyl (eg, 2H-tetrazol-5-yl-methyl), amine C _1-4 alkyl (eg amine-ethyl), C _1-4 alkoxy (eg methoxy), -C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H ) S (O) 2 -CH 3) or _{-N (R 8) (R 9} ) ^2, heteroaryl (e.g., substituted with , Pyrid-3-yl), or a compound of Formula II (A) or any 2.1-2.3;

2.5 A is a compound of Formula II (A) or any of 2.1-2.3, which is heteroaryl ² (eg, pyrid-3-yl) optionally substituted with one or more C _1-4 alkoxy (eg, methoxy);

2.6 A is a compound of Formula II (A) or any 2.1-2.3, wherein 2-methoxy-pyrid-3-yl;

2.7 Substituents Alk, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently formulas II (A) described in 1.1-1.4 and 1.16-1.38, Or any of 2.1-2.6;

2.8 A compound of Formula (II) wherein the compound is

;

;

2.9 A compound of formula II (A) is bound to an FMN riboswitch, for example an IC ₅₀ of up to 100 μM, preferably less than 75 μM, more preferably in a binding assay as described for example in Example 1 Less than 50 μM, still more preferably less than 25 μM, most preferably less than 10 μM and / or the minimum inhibitory concentration (MIC) of the compound of formula II is 128 μg in an assay as described, for example, in Example 2. Any preceding formula in the form of a free, salt or prodrug that is less than / ml, preferably less than 100 µg / ml, more preferably less than 50 µg / ml, still preferably less than 35 µg / ml.

In a fourth embodiment, the invention relates to compounds of formula I (B) in free or salt form:

<Formula I (B)>

In the above formulas,

(i) Alk is C _1-2 alkylene (eg methylene or ethylene);

(ii) X is -N (R ₆ )-,

(iii) A is

-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),

-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, tetrazolyl, pyridyl, indolyl, 1,2, 5-oxadiazolyl, pyrrolyl) wherein the alkyl group of the -alkylaryl ¹ and -alkylheteroaryl ¹ is optionally substituted with hydroxy or another aryl (e.g. phenyl) and the -alkylaryl ¹ and -alkylhetero aryl ^{1 1} aryl and heteroaryl ¹ group is at least one

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

        -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );

-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;

-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);

-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);

-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);

-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);

-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);

-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);

-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;

-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl;

Para-phenylbenzyl;

(iv) R ₁ is H or C _1-4 alkyl (eg methyl);

(v) R ₂ is selected from the group consisting of H, C _1-4 alkyl (eg methyl) and —OC _3-8 cycloalkyl ¹ (eg —O-cyclopentyl);

(vi) R ₆ is H or C _1-4 alkyl (eg methyl);

(vii) R ₁₁ and R ₁₂ are independently H or C _1-4 alkyl (eg methyl).

The present invention further relates to compounds of formula (I) as follows in free or salt form:

3.1 Alk is a compound of Formula I (B) wherein C _1-2 alkylene (eg methylene or ethylene);

3.2 Alk is ethylene; or a compound of Formula I (B) or 3.1;

3.3 A

-C _1-4 alkyl-N (R ₅ ) (R ₆ ),

-C _0-4 alkyl ¹ -aryl (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, tetrazolyl, pyridyl, indolyl, 1,2, 5-oxadiazolyl, pyrrolyl), wherein the alkyl group of -alkylaryl ¹ and -alkylheteroaryl ¹ is optionally substituted with hydroxy or another aryl ¹ (e.g., phenyl) and the -alkylaryl ¹ and -alkyl aryl and ^{1-heteroaryl 1-heteroaryl 1} group is at least one

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

          -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg morpholinyl),

          Aryl (e.g., phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );

-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;

-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);

-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);

-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);

-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);

-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);

-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);

-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;

-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl;

A compound of Formula (I) or any of 3.1-3.2, selected from the group consisting of para-phenylbenzyl;

3.4 A is

-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, tetrazolyl, pyridyl, indolyl, 1,2, 5-oxadiazolyl, pyrrolyl), wherein the alkyl group of -alkylaryl ¹ and -alkylheteroaryl ¹ is optionally substituted with hydroxy or another aryl ¹ (e.g., phenyl) and the -alkylaryl ¹ and -alkyl aryl and ^{1-heteroaryl 1-heteroaryl 1} group is at least one

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

          -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );

-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);

-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);

-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);

-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);

-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);

-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);

-C _0-4 alkyl optionally substituted by -C _0-4 alkyl-pyrrolyl (e.g., 1-methyl-pyrrol-2-yl-methyl) The compound of Formula I (B) or compounds of any of 3.1-3.2 selected from the group consisting of ;

3.5 A is

-C _0-4 alkyl-aryl ¹ (for example, phenyl, naphthyl, benzyl) wherein the - alkyl group of the alkyl aryl is optionally substituted with ^one hydroxy or ^one another aryl (e.g., phenyl), wherein the-aryl alkyl ¹ , aryl group is one or more

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

        -OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );

-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);

-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);

-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);

-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);

-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);

-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);

-C _0-4 alkyl optionally substituted by -C _0-4 alkyl-pyrrolyl (e.g., 1-methyl-pyrrol-2-yl-methyl) The compound of Formula I (B) or compounds of any of 3.1-3.2 selected from the group consisting of ;

3.6 A is -C _1-4 alkyl-N (R ₅ ) (R ₆ ) and R ₅ and R ₆ are independently H or C _1-4 alkyl (eg methyl) or any of Formula I (B) The compound of 3.1-3.2;

3.7 A is Formula 3.6, wherein -CH ₃ (CH ₂ ) ₃ -NH ₂ ;

3.8 A is Formula 3.6 wherein dimethylaminoethyl (-CH ₃ CH ₂ -N (CH ₃ ) ₂ );

3.9 A is -C _{0 - 4} alkyl-aryl ¹ (for example, phenyl, naphthyl, benzyl), or -C _{0 - 4} alkyl-heteroaryl ¹ (for example, isoxazolyl, tetrazolyl, pyridyl, indolyl, 1 , 2,5-oxadiazolyl, pyrrolyl), wherein the alkyl group of -alkylaryl ¹ and -alkylheteroaryl ¹ is optionally substituted with hydroxy or another aryl ¹ (e.g., phenyl), and -alkylaryl and ^{1-alkyl-heteroaryl} group aryl and ^{1-heteroaryl 1} of the ^first one or more of

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

-OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

-SO ₂ -C _{1 - 4} alkyl (e.g., -SO ₂ -CH ₃₎ by the formula I (B) or compounds of any of 3.1-3.2 substituted independently;

3.10 A is —C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl), wherein the alkyl group of the -alkylaryl is optionally substituted with hydroxy or another aryl (eg phenyl), and The aryl group of the alkylaryl is one or more

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

-OH,

Heteroaryl ² (eg imidazolyl),

HeteroC _3-8 cycloalkyl ² (eg, morpholinyl),

Aryl ² (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

-SO ₂ -C _{1 - 4} alkyl (e.g., -SO ₂ -CH ₃₎ the general formula I (B) or compounds of any of 3.1-3.2 is substituted by;

3.11 A is —C _0-4 alkylphenyl (eg phenyl or benzyl), wherein phenyl is one or more

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

-OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl ¹ (eg phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

-SO ₂ -C _{1 - 4} alkyl (e.g., -SO ₂ -CH ₃₎ substituted Formula 3.10;

3.12 A is —C _0-4 alkylphenyl (eg phenyl or benzyl) wherein phenyl is formula 3.10 substituted with —O-halo-C _1-4 alkyl (eg —OCF ₃ );

3.13 A is benzyl substituted with —OCF ₃ Formula 3.10;

3.14 A is —C _0-4 alkylphenyl (eg, phenyl or benzyl), wherein phenyl is a formula 3.10 substituted with —NO ₂ ;

3.15 A is formula 3.10 wherein m-nitrobenzyl;

3.16 A is —C _0-4 alkylphenyl (eg phenyl or benzyl), wherein phenyl is formula 3.10 substituted with another aryl ² (eg phenyl);

3.17 A is p-phenylbenzyl Formula 3.10;

3.18 A is —C _0-4 alkylphenyl (eg phenyl or benzyl), wherein phenyl is formula 3.10 substituted with —SO ₂ —C _1-4 alkyl (eg —SO ₂ —CH ₃ );

3.19 A is Formula 3.10, wherein 3-methylsulfonylbenzyl;

3.20 A is —C _0-4 alkyl-heteroaryl ¹ (eg, isoxazolyl, tetrazolyl, pyridyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl), wherein said -alkylheteroaryl alkyl group is optionally substituted with ^one hydroxy or ^one another aryl (e.g., phenyl), wherein - ^one of the heteroaryl-alkyl heteroaryl groups one or more of

-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,

-OH,

Heteroaryl ¹ (eg imidazolyl),

HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),

Aryl (e.g., phenyl),

-O-halo-C _1-4 alkyl (eg -OCF ₃ ),

-NO ₂ ,

-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,

-SO ₂ -C _{1 - 4} alkyl (e.g., -SO ₂ -CH ₃₎ the general formula I (B) or the compound of any substituted with from 3.1 to 3.10;

3.21 Formula 3.20, A is a substituted -C _0-4 alkyl -1,2,5- oxadiazolyl to at least one of substituents as described in the above 3.20;

3.22 A, wherein Formula 3.20 is 3-methyl-1,2,5-oxadiazol-4-ylmethyl;

3.23 A is a formula 3.20, which is —C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl), substituted with one or more hydroxy;

3.24 A, wherein Formula 3.23 is 2-hydroxypyrid-4-ylmethyl;

3.25 A is -C _{0 - 4} alkyl-benzotriazolyl (for example, 1H- benzotriazole-5-yl), of the formula I (B) or compounds of any of 3.1 to 3.10;

3.26 A of Formula I (B) or any of 3.1-3.10, wherein A is -C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl) compound;

3.27 A is -C _{0 - 4} alkyl-tetrazolyl (e.g., 1,2,3,5- tetrahydro-4-ylethyl) of the formula I (B) or compounds of any of 3.1 to 3.10;

3.28 A is -C _{0 - 4} alkyl-oxadiazolyl (e.g., 1,2,5-oxadiazol-3-yl), of the formula I (B) or compounds of any of 3.1 to 3.10;

3.29 A is -C _{0 - 4} alkyl-benzo-dioxide solril (e.g., 1, 3-benzodioxol-5-ylmethyl) of the formula I (B) or compounds of any of 3.1 to 3.10;

Formula is benzimidazolyl (for example, 1-methyl-benzimidazol-2-yl-methyl, benzimidazol-5-ylmethyl) - 3.30 A is -C _0-4 alkyl optionally substituted with -C _0-4 alkyl, I (B) or a compound of any of 3.1-3.10;

3.31 A is a compound of Formula I (B) or any of 3.1-3.10, wherein -C _0-4 alkyl-imidazolyl (eg, 1-methyl-imidazol-5-ylmethyl is optionally substituted with C _1-4 alkyl) ;

3.32 A is -C _0-4 alkyl optionally substituted with -C _0-4 alkyl-pyrrolyl (e.g., 1-methyl-pyrrol-2-ylmethyl) of the formula I (B) or compounds of any of 3.1 to 3.10;

3.33 R ₁ is H or C _{1 - 4} alkyl (such as methyl) of the formula I (B) or compounds of any of 3.1 to 3.32;

3.34 A compound of Formula I (B) or any 3.1-3.32, wherein R ₁ is methyl;

3.35 R ₂ is Formula I (B) or any 3.1-3.34 selected from the group consisting of H, C _1-4 alkyl (eg methyl) and —OC _3-8 cycloalkyl ¹ (eg —O-cyclopentyl) Compound of;

3.36 Formula 3.35, wherein R ₂ is H;

The Formula 3.35 ₄ alkyl (such as methyl) _- 3.37 R ₂ is C _1;

3.38 R ₂ is -OC _{3 -} in Formula ¹ 3.35 ₈ cycloalkyl (for example, -O- cyclopentyl);

3.39 Formula 3.35, wherein R ₁ is C _1-4 alkyl (eg methyl) and R ₂ is —OC _3-8 cycloalkyl ¹ (eg —O-cyclopentyl);

The Formula 3.35 ₄ alkyl (such as methyl) _- 3.40 R ₁ and R ₂ are C _1;

3.41 Formula 3.35, wherein R ₁ and R ₂ are methyl;

3.42 R ₄ is H or C _{1 - 4} alkyl (such as methyl) of the formula I (B) or compounds of any of 3.1 to 3.41;

3.43 Formula 3.42, wherein R ₄ is H;

The Formula 3.42 ₄ alkyl (such as methyl) _- 3.44 R ₄ is C _1;

3.45 R ₅ and R ₆ are independently H or C _{1 - 4} alkyl (such as methyl) of the formula I (B) or compounds of any of 3.1 to 3.44;

3.46 a compound of Formula I (B) or any 3.1-3.45 wherein R ₅ and R ₆ are H;

3.47 R ₅ and R ₆ is C _{1 - 4} alkyl (such as methyl) of the formula I (B) or compounds of any of 3.1 to 3.45;

3.48 and R ₅ is H, R ₆ is C _{1 - 4} alkyl (such as methyl) of the formula I (B) or compounds of any of 3.1 to 3.45;

3.49 A

Benzyl meta or para substituted with -O-halo-C _1-4 alkyl (eg -OCF ₃ );

Indol-3-ylethyl;

1,3-benzodioxol-5-ylmethyl;

1-methylpyrrolidin-2-ylmethyl;

A compound of formula (I) or any of 3.1-3.10 or 3.33-3.48; selected from the group consisting of para-phenylbenzyl;

3.50 A

1,3-benzodioxol-5-ylmethyl,

Benzyl ortho or meta-substituted with -OCF ₃ ,

Benzyl substituted with -NO ₂ ,

A compound of Formula (I) or any of 3.1-3.10 or 3.33-3.48, selected from the group consisting of para-phenylbenzyl;

3.51 Any preceding formula wherein the compound of Formula I (B) is selected from:

3.52 Any preceding formula wherein the compound of Formula I (B) is selected from:

3.53 Any formula 3.1-3.51 wherein the compound of Formula I (B) is selected from:

3.54 The formula 3.1-3.51 wherein the compound of formula I (B) is selected from:

3.55 Compound binds to FMN and / or CD3299 riboswitch and I _max is greater than 20%, preferably greater than 30%, more preferably greater than 40%, still more even in an assay as described for example in Example 1 Preferably it is greater than 50% and / or the minimum inhibitory concentration (MIC) is 64 μg / ml or less, more preferably 32 μg / ml or less, still more preferably in an assay as described in Example 2, for example. Any preceding formula that is 16 μg / ml or less.

In a fourth embodiment, the invention relates to compounds of formula II (B) in free or salt form:

<Formula II (B)>

In the above formulas,

R ₁ is H or C _1-4 alkyl (eg methyl);

R ₂ is selected from the group consisting of H, C _1-4 alkyl (eg methyl) and —OC _3-8 cycloalkyl ¹ (eg —O-cyclopentyl);

Y is

로 구성된 군으로부터 선택된다.

It is selected from the group consisting of.

In a further embodiment of the fourth embodiment, the invention relates to compounds of formula II (B) which are in free or salt form selected from any of the following:

In still further embodiments of the fourth embodiment, the invention relates to compounds of formula II (B) which are in free or salt form selected from any of the following:

In a further embodiment of the fourth embodiment, the invention relates to compounds of formula II (B) which are in free or salt form selected from any of the following:

In yet another further embodiment of the fourth embodiment, the invention relates to compounds of formula II (B) which are in free or salt form selected from any of the following:

In another embodiment, the compound of formula II (B) as described above is bound to FMN and / or CD3299 riboswitch, for example I _max is greater than 20%, preferably in an assay as described in Example 1 Is greater than 30%, more preferably greater than 40%, still more preferably greater than 50% and / or the minimum inhibitory concentration (MIC) is 64 μg / ml or less, for example in an assay as described in Example 2, More preferably 32 μg / ml or less, still more preferably 16 μg / ml or less.

In a sixth embodiment, the invention relates to compounds of formula III (B), which are in free or salt form:

<Formula III (B)>

In the above formulas,

(i) R ₁ is H or C _1-4 alkyl (eg methyl);

(ii) R ₂ is selected from the group consisting of H, C _1-4 alkyl (eg methyl) and —OC _3-8 cycloalkyl (eg —O-cyclopentyl);

(iii) R ₄ is benzyl;

(iv) R ₅ is aryl ¹ -C _0-4 alkyl (eg phenyl, benzyl, phenylpropyl), hydroxyC _1-4 alkyl (hydroxybutyl), C _1-4 alkyl (eg n-butyl) , C _3-8 cycloalkyl ¹ (eg cyclopentyl), wherein R ₅ is optionally substituted with one or more hydroxy or C _1-4 alkyl (eg methyl); or

(v) R ₄ is H and R ₅ is 1,2-diphenylethyl or 1-hydroxy-2-hydroxymethyl-2-phenyl (-C (H) (CH ₂ OH) -C (H) (OH) -C ₆ H ₅ ).

In a further embodiment of the sixth embodiment, the invention relates to compounds of formula III (B) selected from any of the following in free or salt form:

In another sixth embodiment, the invention relates to compounds of formula III (B), selected from any of the following in free or salt form:

In another sixth embodiment, the invention relates to compounds of formula III (B), selected from any of the following in free or salt form:

In another sixth embodiment, the invention relates to compounds of formula III (B), selected from any of the following in free or salt form:

In another embodiment, a compound of Formula III (B) as described above is bound to FMN and / or CD3299 riboswitch, for example I _max is greater than 20%, preferably in an assay as described in Example 1 Is greater than 30%, more preferably greater than 40% and / or the minimum inhibitory concentration (MIC) is no greater than 64 μg / ml, for example in an assay as described in Example 2.

In a seventh embodiment, the invention relates to compounds of formula IV (B), selected from any of the following in free or salt form:

Compounds of formula IV (B) as described above are bound to FMN and / or CD3299 riboswitch, for example I _max is greater than 20% and / or minimum inhibitory concentration (MIC) in the assay as described in Example 1 ) Is, for example, 64 μg / ml or less in the assay as described in Example 2.

In an eighth embodiment, the invention relates to compounds of formula V (B), selected from any of the following in free or salt form:

The compounds described herein, i.e., formulas Q, QI, Q-II, Q-III, Q-IV, QV, Q (i), QI (i), Q-II (i), Q- in free or salt form III (i), Q-IV (i), QV (i) , or any of Q.1 - Q.42, I (a) or any of 1.1 - 1.44, II (a) or any of 2.1 - 2.9, I (B) or any of 3.1 - compound of 3.55, II (B), III (B), IV (B), or V (B) shall be referred to as the compounds of the present invention.

In a ninth embodiment, the invention relates to a pharmaceutical composition comprising a compound of the invention in the form of a free or pharmaceutically acceptable salt as described above in admixture with a pharmaceutically acceptable diluent or carrier. In a further embodiment, the pharmaceutical composition of the present invention comprises the following in admixture with a pharmaceutically acceptable diluent or carrier:

(a) a compound of formula Q (i) or any Q.1 - Q.42 (composition Q (i)) in free or pharmaceutically acceptable salt form

(b) a compound of formula QI (i) or any Q.1 - Q.42 (composition QI (i)) in free or pharmaceutically acceptable salt form

(c) a compound of formula Q-II (i) or any Q.1 - Q.42 (composition Q-II (i)) in free or pharmaceutically acceptable salt form

(d) a compound of formula Q-III (i) or any Q.1 - Q.42 (composition Q-III (i)) in free or pharmaceutically acceptable salt form

(e) a compound of formula Q-IV (i) or any Q.1 - Q.42 (composition Q-IV (i)) in free or pharmaceutically acceptable salt form

(f) a compound of formula QV (i) or any Q.1 - Q.42 (composition QV (i)) in free or pharmaceutically acceptable salt form

(g) compounds in free or pharmaceutically acceptable salt form of the formula I (A) (i), for example, any of formulas 1.1 - 1.44 (composition I (A) (i))

(h) compounds in free or pharmaceutically acceptable salt of (A) (II) form, for example, any of 2.1 - 2.9 (composition II (A))

(i) a glass or a pharmaceutically acceptable salt form of a compound of the formula or any of 3.1 I (B) - 3.55 (composition I (B))

(j) Compounds of formula II (B) in free or pharmaceutically acceptable salt form (composition II (B))

(k) Compounds of formula III (B) in free or pharmaceutically acceptable salt form (composition III (B))

(l) a compound of formula IV (B) (composition IV (B)) in free or pharmaceutically acceptable salt form or

(m) A compound of formula V (B) (composition V (B)) in free or pharmaceutically acceptable salt form.

In one embodiment, the pharmaceutical composition of the present invention comprises a compound selected from any one of Formulas 1.39 , 1.41 , 1.42 or 1.43 in free or pharmaceutically acceptable salt form. In another embodiment, the pharmaceutical composition of the invention is in any formula Q.35 , Q.36 , Q.37 , Q.38 , Q.39 , Q.40 or in free or pharmaceutically acceptable salt form Compound selected from those described in Q.41 .

In a tenth embodiment, the invention provides for the treatment of a bacterial infection comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the invention, eg, administering an effective amount of Or to a method for prevention (the method of the invention):

(a) a compound or pharmaceutical composition of formula Q or any Q.1 - Q.42 in the form of a free or pharmaceutically acceptable salt (method Q)

(b) a compound or pharmaceutical composition of formula QI or any Q.1 - Q.42 in the form of a free or pharmaceutically acceptable salt (method QI)

(c) a compound or pharmaceutical composition of formula Q-II or any Q.1 - Q.42 in the form of a free or pharmaceutically acceptable salt (method Q-II)

(d) a compound or pharmaceutical composition of formula Q-III or any Q.1 - Q.42 in the form of a free or pharmaceutically acceptable salt (method Q-III)

(e) a compound or pharmaceutical composition of formula Q-IV or any Q.1 - Q.42 in the form of a free or pharmaceutically acceptable salt (method Q-IV)

(f) a compound or pharmaceutical composition of formula QV or any Q.1 - Q.42 in the form of a free or pharmaceutically acceptable salt (method QV)

(g) an acceptable salt or a pharmaceutically glass form the formula I (A), for example, any of formulas 1.1 - 1.44 of the compound or pharmaceutical composition (method I (A))

(h) free or pharmaceutically acceptable salt forms of the formula II with (A), for example, any of 2.1 - 2.9 of the compound or pharmaceutical composition (method II (A))

(i) a glass or a pharmaceutically acceptable salt form of the formula I (B) or any of 3.1 - 3.55 of the compound or pharmaceutical composition (Method I (B))

(j) A compound or pharmaceutical composition of formula II (B) in free or pharmaceutically acceptable salt form (method II (B))

(k) A compound or pharmaceutical composition of formula III (B) in free or pharmaceutically acceptable salt form (method III (B))

(l) a compound or pharmaceutical composition of formula IV (B) in the form of a free or pharmaceutically acceptable salt (method IV (B)) or

(m) A compound or pharmaceutical composition of formula V (B) in the form of a free or pharmaceutically acceptable salt (method V (B)).

In a further embodiment, the present invention is in need of treating an effective amount of a compound or pharmaceutical composition comprising a compound of any of Formula 1.41 , 1.42 or 1.43 as described above in free or pharmaceutically acceptable salt form. A method for the treatment or prevention of a bacterial infection comprising administering to a subject. In another embodiment, the method of the present invention is any formula Q.35 , Q.36 , Q.37 , Q.38 , Q.39 , Q.40 or Q. in the form of a free or pharmaceutically acceptable salt. It includes any compound described in 41 .

In a further embodiment of the tenth embodiment, the methods of the invention as described above are useful for the treatment or prevention of Gram positive 7 or Gram negative bacterial infection (methods QA, QIA, Q-II-A, Q-, respectively). III-A, Q-IV-A, QVA, I (A) -A, II (A) -A, I (B) -A, II (B) -A, III (B) -A, IV (B ) -A, V (B) -A). In a particular embodiment, the method of the present invention comprises Clostridium difficile (or C. difficile), Moraxella catarrhalis , Klebsiella pneumoniae , star Staphylococcus epidermidis , Streptococcus viridans , Enterococcus paesium , Staphylococcus aureus , Bacillus anthracis , Francis Sella Tullarensis, Streptococcus pneumoniae , Pseudomonas aeruginosa , Acinetobacter baumannii , Brucella melitensis , Escherichia (Escherichia coli), a brush under the loose influenza (Haemophilus influenzae), L. monocytogenes cytokines to Ness (Listeria monocytogenes), Salmonella Entebbe Car (Salmonella enterica), in V. cholera (Vibrio cholerae), Enterobacter nose kusu par faecalis (Enterococcus faecalis), Yersinia pestiviruses switch (Yersinia pestis), Bacillus subtilis, Streptococcus blood comes Ness (Streptococcus pyogenes), and And / or are useful for the treatment of bacterial infections including, but not limited to, infections with one or more of the Borrelia burgdorferi bacteria (methods QB, QIB, Q-II-B, Q-III, respectively). -B, Q-IV-B, QVB, I (A) -B, II (A) -B, I (B) -B, II (B) -B, III (B) -B, IV (B) -B, V (B) -B). In another specific embodiment, the methods of the present invention comprise Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus paesium, Staphylococco Cuus aureus, Bacillus anthracis, Francisella tullarensis, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannini, Brucella melithensis, Eccherichia coli, Haemophilus influenza Among, among, Listeria monocytogenes, Salmonella enterica, Vibrio cholera, Enterococcus paecalis, Yersintia pestis, Bacillus subtilis, Streptococcus piogenes and / or Borelia burgdorfferri bacteria. Useful for the treatment of bacterial infections, including but not limited to infection by species or more (methods Q-B ', QI-B', Q-II-B ', Q-III-B', Q-IV, respectively) -B ', QV-B ', I (A) -B', II (A) -B ', I (B) -B', II (B) -B ', III (B) -B', IV (B) -B ', V (B) -B '). In one embodiment, the method of the present invention comprises Clostridium difficile (or C. difficile), Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus paecalis Among the bacteria that are Streptococcus pneumoniae, Streptococcus piogenes, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, and Acinetobacter Baumannini Useful for the treatment of infections caused by species or more. In another embodiment, the methods of the present invention are useful for treating infection with bacteria that are Staphylococcus aureus and / or Staphylococcus epidermidis. In certain embodiments, the methods of the invention are useful for treating Staphylococcus aureus infections (methods QC, QIC, Q-II-C, Q-III-C, Q-IV-C, QVC, I (A) -C, II (A) -C, I (B) -C, II (B) -C, III (B) -C, IV (B) -C, V (B) -C). Patients who are receiving antibiotics, especially broad-spectrum active treatment, can destroy seeds of normal gut bacteria. C. as a result of the use of antibiotics that cause overgrowth of difficile, causing infections in a range of asymptomatic, severe and life-threatening conditions. It is particularly vulnerable to difficile infections. Various compounds of the present invention are particularly active against CD3299 riboswitches. Selectively inhibits difficile bacteria. Therefore, in certain embodiments, the methods of the present invention are particularly useful for treating infections caused by Clostridium difficile.

In another embodiment of the tenth embodiment, the present invention comprises administering to a subject in need thereof an effective amount of a compound of the present invention as described above in free or pharmaceutically acceptable salt form, Staphylococcal laceration skin syndrome (streptococcus infection), pneumonia, impetigo, boils, cellulitis, folliculitis, furuncle, carbuncle, laceration skin syndrome, abscess, meningitis, osteomyelitis, Endocarditis, Toxic Shock Syndrome (TSS), Sepsis, Acute Sinusitis, Otitis Media, Infectious Arthritis, Endocarditis, Peritonitis, Peritonitis, Cellulitis, Brain Abscess, Yato Disease, Urinary Tract Infection, Livestock, Food Poisoning, Diarrhea, Conjunctivitis, and Clostridium difficile To a method of the invention as described above useful for the treatment or prevention of a disease, infection or condition selected from the group consisting of diseases (CDAD), respectively. Method QD, QID, Q-II-D, Q-III-D, Q-IV-D, QVD, I (A) -D, II (A) -D, I (B) -D, II (B) -D, III (B) -D, IV (B) -D, V (B) -D). In yet another tenth embodiment, the present invention relates to the method QD of the present invention selected from any of those described in Formula 1.39, 1.41 , 1.42 or 1.43 , wherein the compound is in free or pharmaceutically acceptable salt form. In one particular embodiment, the present invention is any formula Q.35 , Q.36 , Q.37 , Q.38 , Q.39 , Q.40 or Q.41 in free or pharmaceutically acceptable salt form. A method QD comprising a compound selected from any of those described herein is provided.

Without wishing to be bound by any particular theory, the present invention modifies gene expression using, for example, riboswitch-ligand binding, and thus treats bacterial infections by novel mechanisms affecting downstream riboflavin biosynthesis. It is about a method. In another embodiment, various compounds of the present invention have activity against CD3299 riboswitches to affect the expression of neighboring coding sites. Compounds having activity against CD3299 ribosewitch are Especially selective for difficile. Thus, a compound of the invention in free or pharmaceutically acceptable salt form as described above, for example a compound selected from any of those described in Formula 1.41 or 1.43 , causes infections in which conventional antibiotics are ineffective due to drug resistance. It is effective in the treatment of. Therefore, in certain embodiments, the present invention relates to the methods of the invention as described above wherein the infection is by an infectious agent that is resistant to a drug that is not a riboswitch ligand (methods QE, QIE, Q-II- respectively). E, Q-III-E, Q-IV-E, QVE, I (A) -E, II (A) -E, I (B) -E, II (B) -E, III (B) -E , IV (B) -E, V (B) -E). In a further embodiment, the infection is resistant to one or more drugs selected from the group consisting of penicillin, vancomycin, cephalosporin and methicillin. In a particular embodiment, the infection is a methicillin-resistant Staphylococcus aureus infection. In yet another embodiment, the infection is resistant to fluoroquinolone (eg, ciprofloxacin- and / or levofloxacin-resistant infection), metronidazole, and / or vancomycin.

It is noted that the various compounds of the present invention have anti-metabolic activity that may interfere with DNA biosynthesis due to low CC ₅₀ values in the assays described in Example 2a. Therefore, in one embodiment, these compounds may be useful as anticancer or antiviral agents. In another embodiment, the compounds having high I _max values and / or low MICs in the assays as described in Examples 1 and 2, respectively, and low CC ₅₀ values in the assays as disclosed in Example 2a are used for topical administration. It is used as an antimicrobial agent.

In an eleventh embodiment, the present invention relates to the use of a compound in the form of a free or pharmaceutically acceptable salt as described above (in the manufacture of a medicament) for the treatment or prevention of an infection, for example a bacterial infection, or of the invention It relates to the use of a pharmaceutical composition comprising a compound (use of the invention). In a further embodiment of the eleventh embodiment, the invention relates to:

a) Use as described above, wherein the compound is a compound of any Formula 1.41 , 1.42 or 1.43 as described above in free or pharmaceutically acceptable salt form.

b) A compound of any of the formulas Q.35 , Q.36 , Q.37 , Q.38 , Q.39 , Q.40 or Q.41 as described above in which the compound is in free or pharmaceutically acceptable salt form Use as described above.

c) Use as described above, wherein the infection is a gram positive or gram negative infection.

d) infections include Clostridium difficile (or C. difficile), Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus paesi Umm, Staphylococcus aureus, Bacillus anthracis, Francisella tullarensis, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter Baumannini, Brusella melithensis, Eshericia collie , Haemophilus influenzae, Listeria monocytogenes, Salmonella enterica, Vibrio cholera, Enterococcus paecalis, Yersinian pestis, Bacillus subtilis, Streptococcus piogenes and / or Borelia burg Use as described above, which is an infection of one or more bacteria selected from the group consisting of dorferi bacteria.

e) Infections of Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus paesium, Staphylococcus aureus, Bacillus anthracis , Francisella Tullarensis, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannini, Brucellella mellitosis, Escherichia coli, Haemophilus influenzae, Listeria monocytogenes, Of at least one bacterium selected from the group consisting of Salmonella enterica, Vibrio cholera, Enterococcus paecalis, Yersinia pestis, Bacillus subtilis, Streptococcus piogenes and / or Borelia burgdorferi bacteria Use as described above which is an infection.

In a preferred embodiment, the infection is Clostridium difficile (or C. difficile), Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus paecalis, Streptococcus 1 type selected from pneumoniae, Streptococcus piogenes, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, and Acinetobacter Baumannini It is due to the above bacteria. In another preferred embodiment, the infection is by Clostridium difficile (or C. difficile), Staphylococcus aureus and / or Staphylococcus epidermidis bacteria.

In a further embodiment of the eleventh embodiment, the present invention relates to anthrax, staphylococcal laceration syndrome (streptococcus infection), pneumonia, impetigo, boil cellulitis, folliculitis, extinction, carbuncle, laceration skin syndrome, abscess, meningitis, osteomyelitis, Endocarditis, toxic shock syndrome (TSS), sepsis, acute sinusitis, otitis media, infectious arthritis, endocarditis, peritonitis, peritonitis, cellulitis, brain abscess, yato disease, urinary tract infection, livestock, food poisoning, diarrhea and conjunctivitis To the use described in the manufacture of a medicament for the treatment or prophylaxis. The invention also relates to the use as described in the eleventh embodiment, wherein the condition, disease or infection is further selected from Clostridium difficile related disease (CDAD).

In another embodiment of the eleventh embodiment, the invention relates to the use as described above, wherein said infection is resistant to a drug which is not a riboswitch ligand. In a further embodiment, the infection is resistant to one or more drugs selected from the group consisting of penicillin, vancomycin, cephalosporin and methicillin. In a particular embodiment, the infection is a methicillin-resistant Staphylococcus aureus infection. In another embodiment, the infection is resistant to fluoroquinolone (eg, ciprofloxacin- and / or levofloxacin-resistant infection), metronidazole, and / or vancomycin.

In a twelfth embodiment, the invention relates to a method of treating infection in a plant comprising administering to the plant an effective amount of a compound of the invention as described above in free or pharmaceutically acceptable salt form. In a further embodiment of the twelfth embodiment, the compound is a compound selected from formula 1.39 or any of the formulas 1.41 , 1.42 or 1.43 as described above in free or salt form. In another embodiment, the infection in said plant is a bacterial infection. In a particular embodiment, the compound is selected from any of those described in Formula 1.41 or 1.43 .

In yet another embodiment, the method according to the twelfth embodiment of the invention provides formulas Q.35 , Q.36 , Q.37 , Q.38 , Q.39 , in the form of free or pharmaceutically acceptable salts. Administering to the plant an effective amount of a compound of Q.40 or Q.41 .

DETAILED DESCRIPTION OF THE INVENTION

The term “riboswitch” or “riboswitches” is a term recognized in the art and means an mRNA comprising a natural aptamer that binds to an expression platform that modulates genes by altering target metabolites and RNA structure.

The term "FMN ribonucleic switch" is flavin mono nucleotide engage the metabolites such as (FMN) or various compounds or Formula in free or salt form of formula I (A) 1.1 - various compounds of 1.44, for example, Formula 1.41 or 1.43, or a compound selected from any of the according to formula II (a), for example as described above as formula 2.1 - 2.9 variety of compounds of formula Q, formula QI) to (QV or formula of Q.1 - Q.42 or formula I (B)) to (V (B) a variety of compounds or formula 3.1, as above-described in-affecting down by bonding a ligand such as a variety of compounds of the present invention including the various compounds of 3.55 streams FMN biosynthesis and transport protein It means a ribo switch.

An "FMN riboswitch ligand" is in free or salt form, for example, which binds to an FMN riboswitch via an FMN-binding aptamer called an RFN element, a highly conserved domain in the 5'-untranslated region of prokaryotic mRNA. It described formula 1.41, or a compound selected from any of the according to formula (II), or 1.43 or 2.1 as described-various compounds of formula 2.9, or Q, QI to QV or Q.1 - various compounds or formula I (B) of Q.22 to Reference is made to various compounds of the formula V (B), various compounds of the invention, such as various compounds of Formulas 3.1 to 3.55 , FMN or roseoflavin. Without wishing to be bound by any particular theory, binding a ligand to its riboswitch is conformational in bacterial mRNA such that ORF expression is inhibited, eg, riboflavin and the enzymes responsible for FMN biosynthesis are inhibited. It has been found to cause change. This can lead to mRNA forming (1) terminator hairpins that stop RNA synthesis before ORF can be synthesized or (2) hairpins that isolate the Shine-Dalgarno sequence and prevent ribosomes from binding to the mRNA and translating the ORF. Is achieved.

"CD3299 riboswitch" is a seed that regulates the gene represented by CD3299. Refers to riboswitches found in difficile. Seed. Starting from ORF from CD3299 gene of difficile 630, accession number AM180355 and 5′UTR are as follows:

SEQ ID NO 1:

In the illustration of the sequence, riboswitches are highlighted in bold, as follows:

SEQ ID NO: 2:

The ORF starting site in this sequence is downstream from the riboswitch, indicated in italics, as follows:

SEQ ID NO: 3:

Provisional terminator hairpins are indicated in bold italics and are as follows:

SEQ ID NO 4:

The hairpin may form a loop having a structure as shown in Formula 1 below.

<Formula 1>

Possible anti-terminators have a structure as shown in Formula 2:

<Formula 2>

Applicants have found that various compounds of the present invention, in particular in the form of free or salts, are well suited to CD3299 riboswitches for the compounds of formula Q or any QI to QV, for example Formula Q.39 , Q.40 or Q.41 . Are combined, Mr. It has been shown to have antimicrobial activity against difficile.

The term "infection" refers to a bacterial infection. In another embodiment, the infection is a gram positive or gram negative infection. In yet another embodiment, the infection is Clostridium difficile, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus paesium, Staphylococcus aureus, Bacillus anthracis, Francisella tullarensis, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannini, Brusella mellitosis, Eshericia coli, Hae Mophilus influenzae, Listeria monocytogenes, Salmonella enterica, Vibrio cholera, Enterococcus paecalis, Yersinian pestis, Bacillus subtilis, Streptococcus piogenes and / or Borelia burgdorfferri Infection by one or more bacteria selected from the group consisting of: In a preferred embodiment, the infection is Clostridium difficile, and / or Staphylococcus aureus and / or Staphylococcus epidermidis infection. In a further embodiment, the infection is Staphylococcus aureus and / or Clostridium difficile infection. In certain embodiments, the infection is an infection that is resistant to drugs that are not ribosewitch ligands. In a further embodiment of this particular embodiment, the infection is an infection that is resistant to one or more drugs selected from the group consisting of penicillin, vancomycin, cephalosporin and methicillin. In a particular embodiment, the infection is methicillin-resistant Staphylococcus aureus (MRSA) infection. In another particular embodiment, the infection is fluoroquinolone-resistant (eg, ciprofloxacin- and / or levofloxacin-resistant), metronidazole, and / or vancomycin-resistant seed. Difficile infection.

The term "bacteria" or "bacterial" includes Clostridium difficile, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus paesium , Staphylococcus aureus, Bacillus anthracis, Francisella tullarensis, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannini, Brusella mellitosis, Eshericia collie, Haemophilus influenzae, Listeria monocytogenes, Salmonella enterica, Vibrio cholera, Enterococcus paecalis, Yersinian pestis, Bacillus subtilis, Streptococcus piogenes and / or Borelia burgdor Ferries may be included, but are not limited thereto. Preferably, the bacterium referred to in the present invention is Clostridium difficile, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus paesium , Staphylococcus aureus, Bacillus anthracis, Francisella tullarensis, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannini, Brusella mellitosis, Eshericia collie, Haemophilus influenzae, Listeria monocytogenes, Salmonella enterica, Vibrio cholera, Enterococcus paecalis, Yersinian pestis, Bacillus subtilis and Streptococcus piogenes It doesn't happen. Bacteria referred to herein are more preferably Clostridium difficile, Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus paecalis, Streptococcus pneumoniae. Examples include, but are not limited to, Streptococcus piogenes, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, and Acinetobacter Baumannini. Most preferably the bacteria referred to herein include Clostridium difficile, Staphylococcus aureus and / or Staphylococcus epidermidis.

Unless otherwise specified or apparent from the context, terms as used herein are as follows:

a. "Alkyl" as used herein is linear or branched (e.g., n-butyl or tert-butyl) unless otherwise indicated, and at any one of the carbon atoms, e.g. C _1-4 alkyl (Eg, methyl), C _1-4 alkoxy, halogen (eg chloro or fluoro), haloC _1-4 alkyl (eg trifluoromethyl), hydroxy and carboxy, for example For example mono-, di- or tri-substituted, for example 1-8, for example 1-6, for example 1-4, in some cases 1-2 carbon atoms in length. Saturated or unsaturated, preferably saturated hydrocarbon moiety. For example “C ₁ -C ₈ alkyl” refers to alkyl having 1 to 8 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 3-methylpentyl, 4-methylpentyl, n-pentyl, n -Hexyl and n-heptyl.

b. “Aryl ² ” as used herein is for example C _1-4 alkyl (eg methyl), C _1-4 alkoxy, halogen (eg chloro or fluoro), haloC _1-4 alkyl (eg Trifluoromethyl), hydroxy, carboxy or monocyclic aromatic hydrocarbon optionally substituted with further aryl ² or heteroaryl ² , preferably phenyl.

c. “Cycloalkyl ² ” is intended to include monocyclic, fully or partially saturated aliphatic (non-aromatic) ring systems such as C _3-8 cycloalkyl ² (eg cyclopentyl or cyclohexyl). Therefore, "cycloalkyl ² " may simply represent cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and the like. Wherein the carbon atom of cycloalkyl ² is optionally substituted with one or more N, O, S, S (O) ₂ or —C (O) —, ie heterocycloalkyl ² , wherein the heterocycloalkyl ² is Examples include piperidinyl (eg piperidin-1-yl), pyrrolidinyl (eg pyrrolidin-1-yl), piperazinyl (eg 2,5-dioxopiperazin-1-yl) Isoxazolidinyl (isoxazolidin-5-yl), 1,1-dioxo-1,4-thiazinan-4-yl, 2-oxopyrimidin-1-yl or 2,4-di Oxo-imidazol-3-yl. ² cycloalkyl or heterocycloalkyl ² of the present invention may be substituted for example with C _1-8 alkyl (e.g., methyl). The above list of substituents is intended to provide specific examples and is not meant to be a complete list.

d. As used herein, “heteroaryl ² ” refers to a monocyclic aromatic ring system comprising one or more heteroatoms independently selected from the group consisting of N, O and S. Heteroaryl ² rings may be bonded to their side chain groups at any heteroatom or carbon atom to produce a stable structure. Heteroaryl ² rings described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. Non-limiting examples of heteroaryl ² groups include pyridyl (eg, pyrid-4-yl or pyrid-3-yl), imidazolyl, thiazolyl, pyrazinyl, pyrimidinyl, and the like. Heteroaryl ² groups may also be optionally substituted, for example with C _1-4 alkyl (eg methyl), C _1-4 alkoxy, halogen, hydroxy, haloC _1-4 alkyl or carboxy.

e. As used herein, “aryl ¹ ” is for example C _1-4 alkyl (eg methyl), C _1-4 alkoxy, halogen (eg chloro or fluoro), haloC _1-4 alkyl (eg Trifluoromethyl), hydroxy, carboxy or monocyclic or polycyclic aromatic hydrocarbons optionally substituted with further aryl or heteroaryl, preferably phenyl.

f. "Cycloalkyl ¹ " is intended to include monocyclic or polycyclic, fully or partially saturated, non-aromatic ring systems, preferably 3 to 8 carbon atoms in length. Therefore, "cycloalkyl ¹ " may simply refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.

g. As used herein, “heteroaryl ¹ ” refers to a monocyclic or polycyclic aromatic ring system comprising one or more heteroatoms independently selected from the group consisting of N, O and S. The heteroaryl ¹ ring may be bonded to its side chain group on any heteroatom or carbon atom that will result in a stable structure. Heteroaryl rings described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. Non-limiting examples of heteroaryl groups include pyridyl (eg, pyrid-4-yl or pyrid-3-yl), imidazolyl, thiazolyl, pyrazinyl, pyrimidinyl, and the like. Heteroaryl groups may also be optionally substituted with C _1-4 alkyl (eg methyl), C _1-4 alkoxy, halogen, hydroxy, haloC _1-4 alkyl or carboxy.

h. Substituents are substituted via alkyl chains such as -C _0-4 alkyl-aryl, -C _0-4 alkyl-heteroaryl, -C _0-4 alkyl-benzotriazolyl or any similar type of substituents described herein. And when connected, it is to be understood that the substituents may be linked via any position on the alkyl chain and need not necessarily be bonded at the terminal carbon of the chain. For example, when the substituent is -C ₃ alkylaryl (eg phenylpropyl), the substituent is -CH ₂ CH ₂ CH ₂ -C ₅ H ₆ or -C (H) (CH ₃ ) -CH ₂ -C ₅ H ₆ , —C (CH ₃ ) (CH ₃ ) —C ₅ H _6, or —C (H) (CH ₃ ) —CH ₂ —C ₅ H ₆ . When the substituent is —C ₀ alkylaryl, C ₀ is intended to be a single bond.

Substituents in the compounds of the present invention, for example Alk, X, Y, A and R ₁ -R ₁₂ may be specifically or generally defined. Unless stated otherwise, Alk, X, A and R ₁ -R ₁₂ are of the formula Q, QI, Q-II, Q-III, Q-IV, QV, Q (i), QI (i), Q -II (i), Q-III (i), Q-IV (i), QV (i) , or any of Q.1 - Q.42, i (a) or any of 1.1 - 1.44, II (a) or any of 2.1 - are as defined in 3.55, II (B), III (B), IV (B) , or V (B) - 2.9, I (B) or any of 3.1.

The compounds of the compounds of the invention (e.g., formula I (A) as described above, for example, any of 1.1 - 1.44, for the compound, for example of formula I (A) (i) the compound or formula II (A) of Any 2.1 to 2.9 or a compound of formula Q, QI to QV, Q (i), QI (i) to QV (i) or any Q.1 to Q.42 or formula I (B) to V (B) of the compound or any of formulas 3.1 - 3.55) may be present as a glass, a salt, for example an acid addition salt or prodrug form. Acid addition salts of compounds of the invention that are sufficiently basic are, for example, inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, toluene sulfonic acid, propionic acid, Succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, Acid addition salts with methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid and the like. In addition, salts of the compounds of the present invention which are sufficiently acidic are alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or salts with organic bases which provide physiologically acceptable cations such as methyl Salts with amines, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine. In certain embodiments, the salt of a compound of the invention is a trifluoroacetic acid addition salt. In another embodiment, the salt of a compound of the invention is an acetic acid addition salt.

In this specification, unless otherwise indicated, terms such as a compound of the present invention refer to compounds that are in any form, such as free or acid addition salts or prodrug forms or base addition salts when the compound includes an acidic substituent. It is to be understood as encompassing. Since the compounds of the present invention are intended for use as medicaments, pharmaceutically acceptable salts are preferred. Salts that are inappropriate for pharmaceutical use may be useful and are intended to be included, for example, for the isolation or purification of free compounds of the invention.

Compounds of the present invention may comprise one or more chiral carbon atoms. Thus, the compounds exist as individual isomers, such as enantiomeric or diastereoisomeric forms or as mixtures of individual forms, for example as racemic / diastereomeric mixtures. Any isomer may exist where the asymmetric center is in the (R)-, (S)-, or (R, S) -configuration. It is understood that the present invention includes all of the respective optically active isomers and mixtures thereof (eg racemic / diastereomeric mixtures). Thus, the compounds of the present invention are generally in, for example, pure or substantially pure isomeric forms, such as greater than 70% enantiomeric excess ("ee"), preferably greater than 80% ee, more preferably greater than 90% ee, Most preferably greater than 95% ee. Purification of the isomers and separation of the isomer mixtures can be carried out by standard techniques known in the art (eg, column chromatography, preparative TLC, preparative HPLC, simulated mobile phase, etc.).

Geometric isomers due to the nature of the double bond or substituents around the ring may exist in cis (= Z-) or trans (= E-) form, both of which are within the scope of the present invention.

As will be appreciated by those skilled in the art, the compounds of the present invention may exhibit keto-enol tautomerization. Therefore, it is to be understood that the invention as defined herein encompasses both the structure as described herein and tautomeric forms thereof.

In addition, the compounds of the present invention are intended to encompass their stable isotopes. For example, hydrogen atoms at certain positions in the compounds of the present invention may be substituted with deuterium. The activity of a compound comprising such isotopes may be retained and / or may have modified pharmacokinetic or pharmacodynamic properties. In addition to therapeutic uses, compounds comprising such isotopes and having modified pharmacokinetic or pharmacodynamic properties may also have utility for measuring the pharmacokinetics of non-isotope analogs.

The compounds of the present invention may in some cases also exist in prodrug form. The term “prodrug” is a term recognized in the art and refers to a drug precursor prior to administration, but generates or releases an active metabolite in vivo after administration through some chemical or physiological process. For example, if a compound of the present invention comprises a carboxy group, these substituents are esterified to yield physiologically hydrolyzable and acceptable esters (eg, carboxylic acid esters, such as -C (O) OR ₇ ). Can be formed. As used herein, "physiologically hydrolysable and acceptable esters" are hydrolyzed under physiological conditions to produce acids, such as carboxylic acids (for compounds of the invention having carboxy substituents) on the one hand. And, on the other hand, by itself means esters of the compounds of the invention which are physiologically tolerable at the dosage. Likewise, when the compound of the present invention comprises an amine group, prodrugs of such amines may also be present, such as amino acids, carbamic acid esters, amide prodrugs, where the prodrugs are degraded in vivo after administration to form active amines. Releases metabolites Further details of amine prodrugs can be found in Jeffrey P. Krise and Reza Oliyai, Biotechnology: Pharmaceutical Aspects, Prodrugs , Volume 5, Part 3, pages 801-831, the contents of which are incorporated by reference in their entirety. Which is incorporated herein by reference. As will be appreciated, the term encompasses conventional pharmaceutical prodrug forms.

For clarity, compounds of formula I (A) (i) have R ₁ being C _1-8 when R ₂ is chloro, Alk is propylene, X is a single bond, and A is pyrrolidin-1-yl Alkyl (eg methyl) or R ₁₀ is —C _1-4 alkyl-OC (O) CH ₃ (eg —CH ₂ OC (O) CH ₃ ), ie the compound of formula (A) is A compound of formula (A), for example, optionally containing a proviso that is not chloro-10- (3-pyrrolidin-1-ylpropyl) benzo [g] pteridine-2,4-dione Formula 1.1 is intended to cover the compounds described in 1.44. Compounds of formula (I) are intended to encompass similar compounds except that compounds of formula (I) do not contain any proviso. Similarly, the compound of formula QI (i)

(a) when R ₂ is chloro, Alk is propylene, X is a single bond, and A is pyrrolidin-1-yl, then R ₁ is C _1-8 alkyl (e.g. methyl) or R ₁₀ is- C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ), ie the compound is 8-chloro-10- (3-pyrrolidin-1-ylpropyl) benzo [ g] not pteridine-2,4-dione;

(b) The compound is 10- [3- (3,6-dioxo-1,4-cyclohexadien-1-yl) propyl) -3,7,8-trimethyl-benzo [g] pteridine-2 , 4- (3H, 10H) -dione;

(c) A is not furinyl, for example the compound is optionally substituted 10- [2- (9H-purin-9-yl) ethyl]-, 10- [3- (9H-purin-9-yl) Propyl]-or 10- [6- (9H-purin-9-yl) hexyl] -7,8-dimethyl-benzo [g] pteridine-2,4- (3H, 10H) -dione;

(d) A is not indol-3-yl, for example the compound is 10- [3- (1H-indol-3-yl) ethyl]-or 10- [3- (1H-indol-3-yl) Propyl] -7,8-dimethyl-benzo [g] pteridine-2,4- (3H, 10H) -dione;

(e) a compound of formula Q as described above, e.g., any Q.1 - Q.42 , comprising the proviso that -Alk-XA is not 2- (2-oxocyclopentylidene) ethyl I want to cover.

Methods of Using Compounds of the Invention

The compounds of the present invention can be used in infections, in particular Clostridium difficile, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus paesium, star Philococcus aureus, Bacillus anthracis, Francisella tullarensis, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannini, Brucellella mellitosis, Eccherichia coli, Haemophil Ruth Influenzae, Listeria monocytogenes, Salmonella enterica, Vibrio cholera, Enterococcus paecalis, Yersinian pestis, Bacillus subtilis, Streptococcus piogenes and / or Borelia burgdorferi bacteria It is useful for the treatment of infection by bacteria, including but not limited to. In a preferred embodiment, the bacterium is Clostridium difficile, Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus paecalis, Streptococcus pneumoniae, Streptococcus Cuus Piogenes, E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenzae, and Acinetobacter Baumannini. In another preferred embodiment, the infection is by Clostridium difficile, Staphylococcus aureus and / or Staphylococcus epidermidis bacteria.

Therefore, the present invention formula I, wherein acceptable salt free or pharmaceutical form (A), for example, any of 1.1 - 1.44, formula II (A), for example, any of 2.1 - 2.9, or the formula I (B) , for example, any of 3.1 - in need of treatment an effective amount of a compound of Q.42 - 3.55, or any of formula II (B) -V (B)) or (Q or any of QI to QV or any Q.1 Anthrax infection, Staphylococcus aureus syndrome (streptococcus infection), pneumonia, impetigo, boil, cellulitis, folliculitis, abscess, carbuncle, laceration skin syndrome, abscess, meningitis, osteomyelitis, endocarditis, toxicity Shock syndrome (TSS), sepsis, acute sinusitis, otitis media, infectious arthritis, endocarditis, peritonitis, pericarditis, cellulitis, brain abscess, yato disease, urinary tract infection, animal husbandry, food poisoning, diarrhea, conjunctivitis and Clostridium difficile-related diseases (CDAD) 1 or more of any of It relates to the treatment.

The terms “treatment” and “treating” are therefore to be understood as encompassing the prevention and treatment or amelioration of the symptoms of the disease as well as the treatment of the cause of the disease.

As used herein, the term "individual" includes human or non-human (eg, animal).

Dosages used in the practice of the present invention will of course depend, for example, on the particular disease or condition to be treated, the specific compound of the invention used, the mode of administration and the desired therapy. Administration of a therapeutically active amount of a therapeutic composition is defined as an amount effective at a dosage for the time necessary to achieve the desired result. For example, a therapeutically effective amount of a compound of the invention that reacts with at least a portion of an FMN riboswitch or CD3299 riboswitch may be a factor such as the disease state, age, sex and weight of the individual and the ability of the compound to elicit the desired response in the individual. It may vary. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the urgency of the therapeutic situation. In general, satisfactory results, for example for the treatment of a disease as described above, indicate that it is intended to be obtained by oral administration in a dosage of about 0.01 to 2.0 mg / kg. For larger mammals, such as humans, the daily dosages given for oral administration may therefore be in the range of about 0.75 to 1,500 mg, conveniently administered 2 to 4 times daily or in divided doses. Or is administered in a delayed release formulation. Thus, unit dosage forms for oral administration are, for example, about 0.2 to 75, 250 mg, 1,500 mg, for example about 0.2 or 2.0 to 50, 75, 100, 250, together with a pharmaceutically acceptable diluent or carrier, 500, 750, 1,000 or 1,500 mg of a compound of the present invention. Pharmaceutical compositions comprising the compounds of the present invention can be produced using conventional diluents or excipients and techniques known in the art of pharmaceuticals. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, spray dried dispersions (eg Eudragit L100), and the like. The term "pharmaceutically acceptable carrier" as used herein is intended to include diluents such as saline and aqueous buffer solutions. The compounds of the present invention may be administered in a convenient manner such as by oral administration, aspiration, transdermal application, intravaginal application, topical application, intranasal, sublingual or rectal administration, by injection such as subcutaneous injection, intravenous injection. Depending on the route of administration, the active compound may be coated with a substance that protects the compound from degradation by enzymes, acids and other natural conditions that may inactivate the compound. In a preferred embodiment, the compound can be administered orally. In another embodiment, the compound is administered by topical application

In certain embodiments, the compounds of the invention may be used alone or in combination with other agents, such as agents that facilitate the influx or penetration of the compounds of the invention into cells, such as antimicrobial cationic peptides, such as at or about the same time, At the same time, it may be administered simultaneously or separately. For example, compounds of the present invention with low or weak MIC activity may be administered alone or in combination with membrane enhancers such as antimicrobial cationic peptides. Antimicrobial cationic peptides include (1) disulfide-binding β-sheet peptides; (2) amphiphilic α-helical peptides; (3) extended peptides; Or (4) a peptide containing a loop-structured peptide. Examples of cationic peptides include, but are not limited to, defensin, cecropin, melittins, margarine, indolisidine, bactenesin and protegrin. Other examples of antimicrobial cationic peptides include Friedrich et al., Antimicrob. Agents Chemother . (2000) 44 (8): 2086 human neutrophil defensin-1 (HNP-1), platelet bactericidal protein-1 (tPMP), DNA gyase or protein synthesis inhibitors, CP26, CP29, CP11CN, CP10A , Bac2A-NH ₂ , but is not limited thereto, the contents of which are incorporated herein by reference in their entirety. Further examples of antimicrobial cationic peptides include, but are not limited to, polymyxins such as polymyxin B, polymyxin E or polymyxin nonapeptides. Thus, in another embodiment, the compounds of the present invention may be administered with a polymyxin such as polymyxin B, polymyxin E or polymyxin nonapeptide, preferably polymyxin B.

In yet another embodiment, the compounds of the invention may be used alone or in combination with other antibacterial agents, such as other antifungal or other systemic antibacterial (sterile or bacteriostatic) agents, eg, at the same time or at about the same time, simultaneously, separately Or may be mixed and administered simultaneously. Examples of bacterial agents include agents that inhibit bacterial cell wall synthesis (eg, penicillin, cephalosporin, carbapenem, vancomycin), agents that damage the cytoplasmic membrane (eg, polymyxins as discussed above), synthesis of nucleic acids, or Agents that modify metabolism (eg, quinolone, rifampin, nitrofurantoin), agents that inhibit protein synthesis (aminoglycoside, tetracycline, chloramphenicol, erythromycin, clindamycin), agents involved in folic acid synthesis (Eg, folate-inhibitors), agents that change energy metabolism (eg, sulfonamides, trimetapririm) and / or other antibiotics (beta-lactam antibiotics, beta-lactamase inhibitors). Specific anti-infective agents, in particular antibacterial and antifungal agents, are described in Remington: The Science and Practice of Pharmacy , Chapter 90, pp. 1626-1684 (21st Ed., Lippincott Williams & Wilkins 2005), the contents of which are incorporated herein by reference in their entirety.

Methods of Making Compounds of the Invention

The compounds of the present invention can be produced as described herein and by using the methods exemplified and by similar methods and by methods known in the chemical art. Non-limiting examples of such methods include the following. In the description of the synthetic methods described herein, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experiment time, and work-up procedures, are selected to be the condition standards for reactions which are readily known to those skilled in the art. It should be understood that. Therefore, sometimes, the reaction may be required to be carried out at a high temperature or for a longer time or a shorter time. One skilled in the art of organic synthesis understands that the functional groups present on the various parts of the molecule must be compatible with the proposed agents and reactions. If starting materials for these methods are not available, they may be produced by procedures selected from the chemical art using techniques similar or similar to the synthesis of known compounds. All documents cited herein are hereby incorporated by reference in their entirety.

Synthetic methods for the compounds of the present invention are illustrated below. The importance of the substituents do not specify a different sense, the formula I (A) or any of 1.1 - 1.44, formula II (A), for example, any of 2.1 - 2.9 or Formula Q or any of QI to QV, or any As described above for Q.1 - Q.42 .

X is -N (R ₆ )-, A is as defined in formula (I) or X is a single bond, A is C _5-6 cycloalkyl and the atom bonded to X is nitrogen (e.g. , -XA is piperidin-1-yl or pyrrolidin-1-yl) The compound of formula (A) reacts riboflavin with orthoguadioic acid, where X is HN (R ₆ )-or X is single Is a bond, and A can be produced by reductive amination of intermediate (B) with HXA, which is a cycloalkyl comprising at least one nitrogen atom, to first produce intermediate (B).

Therefore, in one embodiment, the present invention relates to compounds of formula (I), wherein X is -N (R ₆ )-, A is defined in formula (A) or X is a single bond, and A is C _5-6 cycloalkyl, wherein X is X, comprising reductive amination of a compound of Formula B with HXA wherein at least one atom is nitrogen (eg, -XA is piperidin-1-yl or pyrrolidin-1-yl) Is -N (R ₆ )-, A is defined in formula (I) above or X is a single bond and A is C _5-6 cycloalkyl ² , wherein the atom bonded to X is at least nitrogen ( For example, -XA relates to a process for the preparation of compounds of formula I (A), which is piperidin-1-yl or pyrrolidin-1-yl). In a further embodiment, the amination step comprises the use of an acid, for example acetic acid, and the reduction step comprises for example the use of sodium cyanoborohydride or sodium borohydride:

<Formula (B)>

The compound of formula (C ') is reacted with AC (O) -H, for example, methoxyisonicotinaldehyde, in the presence of an acid, for example acetic acid, followed by a reducing agent such as sodium cyanoborohydride, sodium borohydride. And react with lithium hydride to produce a compound of formula (A) wherein X is -N (R ₆ ) -CH _2- .

Compounds of formula II (A) wherein Y is -N (R ₆ ) -C (O)-are activators or coupling agents, for example HATU, BOP, HOBt, HOAt, dicyclohexylcarbodiimide, diisopropyl Carbodiimide, POCl ₃ and the like and a compound of formula (D) in the presence of a base, for example an organic base such as triethylamine or DIPEA, is selected from AC (O) OH, where A is defined in formula (II) Is heteroaryl).

A compound of formula Q wherein Alk is as defined in formula Q above, X is a single bond, A is a monocyclic heteroaryl ² or C _3-8 cycloalkyl ² , and at least one carbon atom of the cycloalkyl ² is substituted Optionally and independently substituted with a substituted nitrogen atom, the alkylated optionally substituted aryl ² nitro amine with a nucleophile (e.g., LG-Alk-XA, where LG = Br or OMs) to obtain a compound of formula (E) It can be produced by reducing the nitro group to afford the diamine of formula (F). The reaction of diamine with alloxane in the presence of boric acid or diboron trioxide gives the desired product of formula Q.

Alternatively, compounds of formula Q (wherein Alk and A are defined in formula Q above and X is a single bond) may be selected from nucleophiles with aryl diamine optionally substituted in the presence of a base (e.g. sodium carbonate) and n-butyl ammonium iodide. Alkylation can be produced to afford the diamine of formula (F). The reaction of diamine with alloxane in the presence of boric acid provides the desired product of formula Q.

Alternatively, the compound of formula Q, where Alk and A are defined in formula Q, X is a single bond, may be substituted with a suitable amine (AX-Alk-NH ₂ ) in the presence of a base (eg CsCO ₃ ) and a palladium catalyst. By reacting with an optionally substituted aryl nitro bromide or alternatively by reacting an amine nit with optionally substituted aryl nitro bromide to give a compound of formula (E). Reduction (eg using sodium borohydride or palladium on carbon with Raney nickel and hydrogen) gives the corresponding diamine of formula (F). The diamine is reacted with alloxane in the presence of boric acid to provide the desired product of formula Q.

Example

Ligand Combination with Ribo Switch :

Example 1 :

As described in Regulski and Breaker, "In-line probing analysis of riboswitches", (2008), Methods in Molecular Biology , Vol 419, pp 53-67, In-line probing assays are described herein. It was used to estimate the dissociation binding constants for the interaction of each of the ligands described in the CD3299 riboswitch amplified from Clostridium difficile or FMN riboswitch amplified from the genome of Bacillus subtilis, the contents of which are incorporated by reference in their entirety. Which is incorporated herein by reference. Precursor mRNA leader molecules were prepared by PCR and [5'-] using the methods described above (Regulski and Breaker, In-line probing analysis of riboswitches (2008), Methods in Molecular Biology Vol 419, pp 53-67). ^It was prepared by in vitro transcription from a template generated by ³² P] -labeling. Approximately 5 nM of labeled RNA precursors were incubated at 25 ° C. for 41 hours in 20 mM MgCl ₂ , 50 mM Tris HCl (pH 8.3 at 25 ° C.) with or without increasing each ligand concentration. In-line degradation products were separated on 10% polyacrylamide gel electrophoresis (PAGE) and the resulting gels were visualized using Molecular Dynamics Phosphorimager. The location of the product band corresponding to degradation was confirmed by comparing partial digests of RNA with RNase T1 (G-specific degradation) or alkali (nonspecific degradation).

In-line probing took advantage of the natural ability of RNA to autolyze at elevated pH and metal ion concentrations (pH 8.3, 25 mM MgCl ₂₎ in a basin-dependent manner. For autolysis to occur, the 2′-hydroxyl of ribose must be “inlined” by phosphate-oxygen bonds of internucleotide linkages that facilitate S _N 2P nucleophilic transesterification and strand degradation. Typically, single-stranded regions of riboswitches are dynamic in the absence of active ligands, and internucleotide linkages in these regions can often allow for the necessary inline alignment. Binding of active ligands to riboswitches generally reduces the kinetics of the region, thereby reducing access to inline loci, thus inducing fewer inline degradation events within that region. These ligand-dependent changes in RNA degradation could easily be detected by denaturing gel electrophoresis. The relative binding affinity of each ligand is expressed as I _max , where I _max is the fixed ligand concentration (20 μM for FMN riboswitch and normalized to inhibition rate in the absence of ligand and presence of saturation concentration of control ligand). Inhibition of inline degradation in a given internucleotide ligand in the presence of 100 μM) for CD3299 riboswitch. 100 μM FMN was used as a control ligand for estimating binding to FMN riboswitches, and 100 μM of standard Compound A (which is a high affinity compound for CD3299 riboswitches) was used to estimate binding to CD3299 riboswitches. Used as control ligand.

Experiments have shown that various compounds of the present invention, especially those described in Formulas 1.41 and 1.43 , have an IC ₅₀ value of 75 μM or less, preferably 50 μM or less, more preferably 25 μM or less, still more preferably 10 μM or less. It was found to have a binding affinity for FMN riboswitches. Further, according to the experiment, a variety of compounds of the invention are for example I _max value of the control binding affinity for FMN ribonucleic switches 20% or more as compared to (i.e., of 100 μM FMN) FIG. Alternatively, the I _max value of the control group (i. E. , 100 μM of Compound A) was found to have a binding affinity for CD3299 riboswitch. In other cases, experiments have shown that various compounds of the present invention bind to CD3299 riboswitches having an I _max value of about 100% at 100 μM, indicating that the compounds of the present invention, as well as the control compounds, are approximately bound. Means that.

MIC Analysis

Example 2 :

MIC analysis was performed with a final volume of 100 μl on 96-well clear round bottom plates according to methods established by the Clinical Laboratory Standards Institute (CLSI). In brief, test compounds suspended in 100% DMSO (or another suitable solubilization buffer) were added to an aliquot of the appropriate medium for the indicated pathogen in a total volume of 50 μl. This solution was serially diluted twice in successive tubes of the same medium to form a range of test compound concentrations suitable for analysis. To the pathogens presented in each dilution of test compounds in the medium, 50 μl of bacterial suspension grown overnight in the appropriate medium was added. Final bacterial inoculum was approximately 10 ⁵ -10 ⁶ CFU / well. After growing for 18-24 hours at 37 ° C., MIC is defined as the lowest concentration of antimicrobial agent that completely inhibits the growth of the organisms detected by the eye compared to the control for bacterial growth in the absence of added antibiotics. Ciprofloxacin was used as an antibiotic-positive control in each screening assay. Each of the bacterial cultures available from the American P. cultivar Collector's Collection (ATCC, www.atcc.org) is identified by its ATCC number.

Experiments have shown that a variety of compounds of the present invention include Clostridium difficile (e.g., C. difficile MMX3581 (clinical) and C. difficile ATCC43596)), Staphylococcus epidermidis, Staphylococcus aureus ( Eg, Staphylococcus aureus ATCC29213 and Staphylococcus aureus RN4220), Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter Baumannini, Haemophilus influenzae, Enterococcus The minimum inhibitory concentration (MIC) for at least one of the bacteria selected from Paecalis and Streptococcus pyogenes is less than 130 μg / ml, in some cases up to 64 μg / ml, and in other cases 32 μg / ml It turned out. For example, these experiments have shown that compounds of Formula I (B) or compounds of Formula Q.39 have a MIC of less than 64 μg / ml.

All of the compounds of the invention exemplified have an I _max value of at least 20% in the assays described in Example 1 (relative to one or more of the two controls at 100 μM) or for FMN riboswitches in the assays described in Example 1 The IC ₅₀ value is 10 μM or less and / or the MIC for one or more of the bacterial strains as described in Example 2 is 128 μg / ml or less. In certain embodiments, certain compounds of the invention have an I _max value of greater than 20% (relative to one or more of the two controls) or an IC ₅₀ value of 10 μM or less for FMN riboswitches in the assays described in Example 1 And / or the MIC for at least one of the bacterial strains as described in Example 2 is 64 μg / ml or less.

Cytotoxicity Assay

Example 2a :

The cytotoxic effect of test compounds on HepG2 was determined using Promega's commercially available cell viability assay kit. On day 1, HepG2 cells (about 1 × 10 ⁴ cells) were seeded into each well in a 96-well plate and incubated under saturated humidity in a 5% CO ₂ atmosphere at 37 ° C. for about 24 hours. On day 2, test compounds and DMSO controls were added to the appropriate wells to produce a range of test compound concentrations suitable for analysis. Terfenadine was also added to each plate as a positive cytotoxic control. Control wells containing the cell free medium were generated to obtain values for background luminescence. The assay plates were then incubated in saturated humidity in a 5% CO ₂ atmosphere at 37 ° C. for about 24 hours. On day 3, the assay plate was removed from the 37 ° C. incubator and equilibrated to 22 ° C. Once equilibrated, the CellTiter-Glo ^® preparation was added to each well containing the cell culture medium and then mixed to allow the cells to lyse. CellTiter-Glo ^® assay determined the number of viable cells in the culture based on the quantification of ATP present, an indicator of metabolic active cells. This analysis produces a luminescent signal that is proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in the culture. After an assay plate was incubated at room temperature for about 10 minutes to stabilize the luminescence signal, luminescence was recorded on a PerkinElmer luminometer. CC ₅₀ is defined as the concentration of test compound (μM) that produces a 50% reduction in the luminescence signal relative to the signal of untreated cells.

Experiments have shown that various compounds of the present invention have a CC ₅₀ value of greater than 7 μg / ml to 45 μg / ml, in some cases at least 30 μM, in certain cases at least 45 μM, and still in other cases at least 65 μM. . In certain cases, various compounds of the present invention have a CC ₅₀ value of greater than 30 μM and a MIC of less than 8 μg / ml.

Synthesis of Compounds of the Invention :

Temperature is given in degrees Celsius (° C.); Operation is carried out at room temperature or room temperature unless otherwise indicated, ie at temperatures in the range 18 ° C. to 25 ° C. Chromatography means flash chromatography on silica gel; Thin layer chromatography (TLC) was performed on silica gel plates. Samples were dissolved in deuterated solvents for NMR spectroscopy. NMR data are expressed as delta values of major diagnostic protons, presented in parts per million (ppm) for the appropriate solvent signal. Conventional abbreviations for signal forms were used. For mass spectra (MS), the lowest mass major ions were recorded for the molecules where isotope splitting produced multiple mass spectral peaks. The solvent mixture composition is presented in volume percentages or volume ratios. If the NMR spectra were complex, only the diagnostic signal was recorded.

General Methods for Analytical HPLC Analysis :

Method A : Analytical HPLC was performed using a Luna Prep C ₁₈ , 100 mm 5 μm, 4.6 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was 0.1% TFA in acetonitrile. Elution profiles are as follows: 95% aqueous (0 to 0.5 minutes); Organic gradient from 95% aqueous to 98% (0.5 to 10.5 min); 98% organic (2 minutes); Gradient from 98% organic to 95% aqueous (5.5 min); 95% aqueous (1 min).

Method B : Analytical HPLC was performed using a Luna Prep C ₁₈ , 100 × 5 μm, 4.6 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was 0.1% TFA in acetonitrile. Elution profiles are as follows: 95% aqueous (0 to 0.5 minutes); Organic gradient from 95% aqueous to 100% (0.5-10.5 min); Gradient from 100% organic to 95% aqueous (2 min); 95% aqueous (4 minutes).

Method C : Analytical LCMS was performed using a YMC Combiscreen ODS-AQ, 5 μm, 4.6 × 50 mm column. The aqueous phase was 1% 2 mM NH ₄ OAc in 90:10 IPA: H ₂ O, 0.03% TFA in USP water. The organic phase was 1% 2 mM NH ₄ OAc in 90:10 IPA: H ₂ O, 0.03% TFA in acetonitrile. The elution profile is as follows: gradient from 95% aqueous to 100% organic (0-10 min); 100% organic (2 minutes); Gradient from 100% organic to 95% aqueous (0.1 min); 95% aqueous (3 min).

Method D : Analytical HPLC was performed using a Luna Prep C ₁₈ , 100 mm 5 μm, 4.6 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was 0.1% TFA in acetonitrile. Elution profiles are as follows: gradient from 95% aqueous to 75% aqueous (0-10 min); Second gradient from 75% aqueous to 98% organic (2.5 min); Third gradient to 95% aqueous (at least 1 minute).

Method E : Analytical HPLC was performed using a Luna Prep C ₁₈ , 100 mm 5 μm, 4.6 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was 0.1% TFA in acetonitrile. Elution profiles are as follows: gradient from 95% aqueous to 40% aqueous (0-10 min); Second gradient from 40% aqueous to 2% aqueous (2 minutes); 2% aqueous (1 min); From 2% aqueous to 95% aqueous (4 minutes).

Method F : Analytical HPLC was performed using a Luna Prep C ₁₈ , 100 mm 5 μm, 4.6 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was 0.1% TFA in acetonitrile. Elution profiles are as follows: gradient from 95% aqueous to 60% aqueous (0-10 min); Second gradient from 60% aqueous to 2% aqueous (2 minutes); 2% aqueous (1 min); From 2% aqueous to 95% aqueous (4 minutes).

System D : Agilent 1100 HPLC, Agilent XDB C ₁₈ 50 × 4.6 mm 1.8 micron column, 1.5 mL / min, solvent A-water (0.1% TFA), solvent B-acetonitrile (0.07% TFA), gradient-5 min 95 95% B from% A; Hold for 1 minute; Then recycle, UV detection at about 210 and 254 nm.

System E : Agilent 1100 HPLC, Agilent XDB C ₁₈ 50 × 4.6 mm 1.8 micron column, 1.5 ml / min, solvent A-water (0.1% TFA), solvent B-acetonitrile (0.07% TFA), gradient-7 min 95 95% B from% A; Hold for 1 minute; Then recycle, UV detection at about 210 and 254 nm.

General Procedure for Preparative HPLC Conditions

Method 1 : Preparative HPLC was performed using a SunFire ™ Prep C ₁₈ OBD ™ 5 μm, 30 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was acetonitrile. Elution profiles are as follows: 100% aqueous (0-3 min); Gradient from 100% aqueous to 98% organic (3 to 21 min); 98% organic (1 min); Gradient from 98% organic to 95% aqueous (1 min); 95% aqueous (1 min).

Method 2 : Preparative HPLC was performed using a SunFire ™ Prep C ₁₈ OBD ™ 5 μm, 30 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was acetonitrile. Elution profiles are as follows: gradient from 95% aqueous to 25% organic (0-10 min); Second gradient from 25% organic to 98% organic (at least 2.5 minutes); Third gradient to 95% aqueous (at least 1 minute).

Method 3 : Preparative HPLC was performed using a SunFire ™ Prep C ₁₈ OBD ™ 5 μm, 30 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was acetonitrile. Elution profiles are as follows: 100% organic (0-3 min); Gradient from 100% aqueous to 60% organic (3 to 21 min); Then gradient to 98% organic (21-24 min); Gradient from 98% organic to 95% aqueous (1 min); 95% aqueous (1 min).

Method 4 : Preparative HPLC was performed using a SunFire ™ Prep C ₁₈ OBD ™ 5 μm, 30 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was acetonitrile. Elution profiles are as follows: gradient from 100% aqueous to 60% organic (0 to 29 minutes); Then gradient to 98% organic (29-31 min); 98% organic (2 minutes); Gradient from 98% organic to 100% aqueous (2 minutes); 100% aqueous (2 minutes).

Terms and abbreviations :

ACN = acetonitrile,

AcOH = acetic acid,

Ar = argon,

Bn = benzyl,

br = wide,

t-BuOH = tert-butyl alcohol,

cat. = Catalytic amount,

CAN = cerium ammonium nitrate (IV),

CBzCl = benzyl chloroformate,

conc. = Dark,

d = doublet,

DCM = dichloromethane,

D-ribose = (2R, 3R, 4R) -2,3,4,5-tetrahydroxypentane,

DIAD = diisopropyl azodicarboxylate,

DIPEA = diisopropylethylamine,

DMF = N, N-dimethylformamide,

DCM = dichloromethane

DMAP = N, N-dimethylaminopyridine,

DMSO = dimethyl sulfoxide,

Et ₂ O = diethyl ether,

Et ₃ N = triethyl amine,

EtOAc = ethyl acetate,

EtOH = ethyl alcohol,

equiv. = Equivalent (s),

Flash chromatography; See Still, WC, Kahn, M .; Mitra, A. J. Org. Chem 1978, 43, 2923,

h = time (s),

H ₂ O = water,

HATU = 2- (1H-7-abenzobenzotriazol-1-yl) -1,1,3,3-tetramethyl uronium hexafluorophosphate methanealuminum,

HBTU = 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate,

HCl = hydrochloric acid,

HPLC = high performance liquid chromatography,

HOAc = acetic acid,

IPA = isopropyl alcohol,

ISCO = normal phase silica gel cartridge supplied by Teledyne ISCO,

K ₂ CO ₃ = potassium carbonate,

LiBH ₄ = lithium tetrahydroborate,

LAH = lithium tetrahydroaluminate,

m = polyline,

min. = Minute (s),

MgCl ₂ = magnesium chloride,

MeOH = methanol

NaHCO ₃ = sodium bicarbonate,

Na ₂ SO ₄ = sodium sulfate,

NH ₄ OH = ammonium hydroxide,

NH ₄ OAc = ammonium acetate,

NMP = N-methylpyrrolidinone,

NMR = nuclear magnetic resonance,

p = quinine,

PMB = p-methoxybenzyl,

POCl ₃ = phosphorus oxychloride,

POMCl = pivaloyloxymethyl chloride,

PPh ₃ = triphenylphosphine,

PyBOP = benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,

rt = room temperature,

RNA = ribonucleic acid,

Endoribonuclease that specifically degrades single-stranded RNA at the RNase T1 = G residue,

s = single line,

SOCl ₂ = thionyl chloride,

t = triplet,

TBAI = tetrabutylammonium iodide,

TFA = trifluoroacetic acid,

TFAA = trifluoroacetic anhydride,

THF = tetrahydrofuran,

TLC = thin layer chromatography,

TMSBr = trimethylsilyl bromide,

Tris HCl = tris (hydroxymethyl) aminomethane hydrochloride,

USP water = US Pharmacopoeia (USP) grade water.

Intermediate 1:

Preparation of 10- (2-aminoethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

Step 1: Preparation of 10- (2- (benzylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde (by the method of step 1, example 3 Produced) and benzylamine, and by reductive amination using a procedure similar to Example 3. The product was contaminated with 10- (2- (benzyl (methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione. Two steps were then performed to separate the product.

Step 2: tert-Butyl benzyl (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) carbamate Manufacture

A solution of crude 10- (2- (benzylamino) ethyl) -7,8-dimethylbenzo [g] -pteridine-2,4 (3H, 10H) -dione (7.53 mmol) in MeOH (200 mL) To di-tert-butyl dicarbonate (5.2 g, 23.8 mmol) and Et ₃ N (4 mL) were added. The reaction was concentrated under reduced pressure and purified over silica gel chromatography (ISCO) (10% MeOH / DCM from 100% DCM) over 1 hour to afford the desired product (1.85 g, 54%) as a brown solid.

Step 3: Preparation of 10- (2- (benzylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetate

Tert-butyl benzyl (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) in DCM (2 mL) To a solution of carbamate (50 mg, 0.11 mmol) was added TFA (2 mL) at room temperature. After 2 hours, the reaction mixture was concentrated and the residual material was dissolved in MeOH (10 mL) and purified by preparative HPLC (Method 2). Lyophilization (LCMS) of the combined pure fractions gave the desired product (33.6 mg, 65%) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.42 (s, 3H), 2.53 (s, 3H), 4.35 (s, 3H), 5.00 (m, 2H), 7.43 (m, 3H), 7.52 ( m, 2H), 7.83 (s, 1H), 7.96 (s, 1H), 9.02 (s, 2H), 11.49 (s, 1H).

Step 4: Preparation of 10- (2-aminoethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione-2,2,2-trifluoroacetate salt

A solution of flavin ethyl benzyl amine (step 3) (395 mg, 1.05 mmol) and Pd / C (75 mg) in anhydrous EtOH (100 mL) was hydrogenated at 30 psi and 45 ° C. overnight. The mixture was filtered through a pad of celite. The filtrate was concentrated to dryness under reduced pressure to give crude product (230 mg, 76.6%). The crude product (19.5 mg, 0.07 mmol) was dissolved in MeOH (8 mL) and preparative HPLC (method 2) was used. Purified. Lyophilization (LCMS) of the combined pure fractions gave the desired product (5.0 mg, 14.3%) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.42 (s, 3H), 2.50 (s, 3H), 4.20 (m, 2H), 4.87 (m, 2H), 7.81 (s, 1H), 7.88 ( m, 2H), 7.97 (s, 1 H), 11.45 (s, 1 H).

Intermediate 2:

1- (3-bromopropyl) -1H-pyrrole

Tribromide tribromide with stirring in a cooled (0-5 ° C.) solution of 3- (1H-pyrrole-1-yl) propan-1-ol (800 mg, 6.39 mmol) in CH ₂ Cl ₂ (30 mL). Fin (3.091 g, 7.03 mmol) was added. After 10 minutes, the ice bath was removed and the mixture was stirred for an additional 3 hours at room temperature. Water was added and the mixture was diluted with CH ₂ Cl ₂ . The layers were separated and the organic layer was washed with brine, dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (230-400 mesh, hexane / ethyl acetate with 0.1% isopropanol as eluent (5%)) to give 630 mg (52%) of the desired product as a clear oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.82 (p, 2 H), 3.33 (t, 2 H), 4.10 (t, 2H), 6.18 (m, 2 H), 6.70 (m, 2 H); HPLC retention time: 3.91 min. (Method G).

Intermediate 3: 1- (3-bromopropyl) -1H-imidazole

Step 1: Preparation of Methyl 3- (1H-imidazol-1-yl) propanoate

To a solution of 1H-imidazole (1.000 g, 14.7 mmol) in acetonitrile (20 mL) was added methyl acrylate (2.65 mL, 29.4 mmol) in a pressurized test tube. The test tube was sealed and heated at 80 ° C. Additional methyl acrylate (1.32 mL, 14.7 mmol) was added after 8 and 12 hours, respectively. After 17 hours, the volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with brine, dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure to give 2.13 g (94%) of the desired product as an oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.80 (t, 2 H), 3.71 (s, 3 H), 4.29 (t, 2 H), 6.94 (s, 1 H), 7.06 (s, 1 H) , 7.52 (s, 1 H); MS (ESI ⁺ ) m / z 155.2 (M + H) ⁺ for C ₇ H ₁₀ N ₂ O ₂ .

Step 2: Preparation of 3- (1H-imidazol-1-yl) propan-1-ol

Tetrahydrofuran (8 mL) was slowly added to a flask containing lithium aluminum hydride (379 mg, 9.99 mmol). The mixture was stirred for 10 minutes at room temperature and then cooled (0 ° C.-5 ° C.). A solution of methyl 3- (1H-imidazol-1-yl) propanoate (770 mg, 4.99 mmol) in THF (3 mL) was added dropwise and the mixture was stirred at 0-5 [deg.] C. for an additional 5 minutes. . The mixture was heated to 70 ° C for 3 h. The mixture was cooled to room temperature and the reaction was terminated by the sequential addition of water (0.38 mL), 15% aqueous NaOH (0.38 mL) and water (1.14 mL). The solid was filtered off through a pad of celite and the filtrate was dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (230-400 mesh, CH ₂ Cl ₂ / methanol (3-5%) as eluent) to give 554 mg (88%) of the desired product as an oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.02 (p, 2 H), 3.63 (t, 2 H), 4.13 (t, 2 H), 6.95 (s, 1 H), 7.07 (s, 1 H) , 7.49 (s, 1 H); MS (ESI ⁺ ) m / z 127.1 (M + H) ⁺ for C ₆ H ₁₀ N ₂ O.

Step 3: Preparation of 1- (3-bromopropyl) -1H-imidazole

Tribromide triphenylphosphine (1.150 g) in a 0 ° C-5 ° C solution of 3- (1H-imidazol-1-yl) propan-1-ol (300 mg, 2.38 mmol) in CH ₂ Cl ₂ (10 mL). , 2.62 mmol) was added with stirring. After 10 minutes, the ice bath was removed and the mixture was stirred for an additional 3 hours at room temperature. Water was added and the reaction mixture was diluted with CH ₂ Cl ₂ . The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried (anhydrous sodium sulfate), filtered and partially concentrated to an approximate volume of 3 ml under reduced pressure. This solution was used immediately for the next step.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.29 (p, 2 H), 2.33 (t, 2 H), 4.18 (t, 2 H), 6.95 (s, 1 H), 7.09 (s, 1 H) , 7.54 (s, 1H).

Intermediate 4: 5- (3-bromopropyl) -3-methylisoxazole

Step 1: Preparation of 3- (3-methylisoxazol-5-yl) propan-1-ol

A solution of 3,5-dimethylisoxazole (2.02 mL, 20.6 mmol) cooled to n-butyllithium (2.5 M in hexane) (8.24 mL, 20.6 mmol) cooled to −78 ° C. under N ₂ in 20 mL THF. Was added. The mixture was stirred at -78 ° C for 2 hours. A solution of ethylene oxide (0.907 g, 20.6 mmol) in 10 mL of THF was added to the mixture at -78 ° C and the mixture was stirred at -78 ° C for 30 minutes. Saturated aqueous NH ₄ Cl was added and the mixture was allowed to warm to room temperature. The pH of the aqueous phase was adjusted to about 7 with 1.0 N HCl and THF was evaporated. The solution was extracted with 3 × 20 mL of CH ₂ Cl ₂ and the combined organic layers were dried over Na ₂ SO ₄ . The organic layer was evaporated to give 1.7 g of oil. The residual 3,5-dimethylisoxazole was removed by drying for 2 hours at room temperature under high vacuum to give 1.3 g (45%) of the desired product as an orange oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.86 (s, 1 H), 3.72 (m, 2 H), 2.85 (t, 2 H), 2.28 (s, 3H), 1.91-2.00 (m, 2 H ), 1.65 (m, 1 H).

Step 2: Preparation of 5- (3-bromopropyl) -3-methylisoxazole

Bromine (0.109 mL, 2.12 mmol) was added to a solution of triphenylphosphine (0.557 g, 2.12 mmol) and pyridine (0.172 mL, 2.12 mmol) in 20 mL of CH ₂ Cl ₂ cooled under N ₂ in an ice bath. . Triphenylphosphine was added until yellow. 3- (3-methylisoxazol-5-yl) propan-1-ol (0.200 g, 1.42 mmol) was added and the mixture was stirred for 15 minutes using an ice bath. The ice bath was removed and the mixture was stirred at rt for 1 h. The mixture was extracted with 3 x 20 ml of 1.0 N aqueous HCl followed by 20 ml of saturated aqueous NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ and evaporated to yield 0.4 g of a white solid. The solid was taken up in 20 mL of hexanes and the solids were removed by filtration through a pad of silica gel (20 g). The pad was eluted with 200 mL of 50% EtOAc / hexanes. Eluent was evaporated to afford 0.22 g (70%) of the desired product as a clear oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.90 (s, 1 H), 3.45 (t, 2 H), 2.93 (t, 2 H), 2.29 (s, 3 H), 2.26 (m, 2 H) .

Example 3

3- (S)-[2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] phthalin-10-yl) -ethylamino]-( Preparation of R) -cyclopentanecarboxylic acid trifluoroacetic acid salt

Step 1: Preparation of 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde

To a suspension of riboflavin (8.5 g, 0.0023 mol) in 2 N aqueous sulfuric acid (225 mL) cooled to 0 ° C. in a flask wrapped with tinfoil, add orthoguadioic acid (18.9 g, 0.0825 mmol) dissolved in water (200 mL). It was. After 30 minutes, the reaction was allowed to warm to room temperature. Once the reaction mixture became clear (clear yellow solution), the pH of the reaction solution was carefully adjusted to 3.8-3.9 (using a pH meter) by adding solid sodium carbonate. (It is important to carefully monitor the pH, and it is important that the product does not precipitate out of solution when the pH exceeds 3.9). The precipitate was then filtered and washed freely with cold water, ethanol and diethyl ether to give 6.04 g of the desired product as an orange solid (yield: 94%). LC-MS mlz 285.1 [M + H] ⁺ , retention time 1.63 minutes.

Step 2: 3- (S)-[2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] putridin-10-yl) -ethylamino Preparation of]-(R) -cyclopentanecarboxylic acid trifluoro-acetic acid salt

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde (100 mg, 0.35 in methanol (10 mL) 3-amino-cyclopentanecarboxylic acid (100 mg, 0.77 mmol) was added to the suspension at room temperature. Glacial acetic acid (7 drops) was added and allowed to stir at room temperature for 3 hours. Sodium cyanoborohydride (48 mg, 0.77 mmol) was added and the solution was stirred for 16 h. The reaction mixture was concentrated and the residue was dissolved in DMSO (5 mL), filtered and purified by preparative HPLC (Method 1). 3- (S)-[2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] phthalin-10-yl) -ethylamino]-( R) -cyclopentanecarboxylic acid (8.2 mg) was isolated after lyophilization of the appropriate fraction (yield: 6.0%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.7 (m, 2H), 1.85 (m, 1H), 2.03 (m, 2H), 2.10 (m, 1H), 2.43 (s, 3H), 2.53 ( s, 3H), 2.90 (m, 2H), 3.73 (m, 2H), 4.92 (m, 2H), 7.78 (s, 1H), 7.98 (s, 1H), 8.66 (m, 2H), 11.49 (s , 1H), 12.35 (s, 1H).

Example 4:

1- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -ethyl] -pyrrolidine-3- Preparation of Carboxylic Acids

1- [2- () produced using the same procedure as in step 2 of the preparation of Example 3, using methyl pyrrolidine-3-carboxylate in a 1: 1 solution of THF: H ₂ O (10 mL). 7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -ethyl] -pyrrolidine-3-carboxylic acid methyl ester ( To a suspension of 25 mg, 0.063 mmol) lithium hydroxide (15 mg, 0.63 mmol) was added at room temperature. The reaction mixture was allowed to stir at room temperature for 15 hours at which point 1 M aqueous HCl (10 drops) was added. The reaction mixture was then concentrated, dissolved in MeOH (6 mL), water (2 mL) and purified by preparative HPLC (Method 1). Lyophilization of the appropriate fractions gave 19 mg of the desired product as a yellow downy solid (yield: 79%). LC-MS mlz 383.0 [M + H] ⁺ , retention time 1.53 minutes.

Example 5:

10- (2-((2-methoxypyridin-4-yl) methylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

10- (2-aminoethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione in MeOH (5 mL) (see intermediate 1 for the preparation) ( 2-methoxyisonicotinaldehyde (produced as in C. Subramanyam, M. Noguchi and SM Weinreb, JOC , 1989, 54, 5580) in a suspension of 46 mg, 0.16 mmol) (22 mg, 0.16 mmol) Then acetic acid (0.1 mL) was added at room temperature. After 30 minutes, sodium cyanoborohydride (30 mg, 0.47 mmol) was added and the solution was stirred for 16 hours. The reaction mixture was concentrated and the residue was dissolved in DMF (4 mL) / water (3 mL), filtered and purified by preparative HPLC (Method 2). Lyophilization of the combined pure fractions afforded the desired product (6.5 mg, 9.7%).

¹ H NMR (400 MHz, CD ₃ OD) δ 2.50 (s, 3H), 2.63 (s, 3H), 3.70 (m, 2H), 3.94 (s, 3H), 4.37 (s, 2H), 5.10 (m , 2H), 6.95 (s, 1H), 7.08 (d, 1H), 7.81 (s, 1H), 7.96 (s, 1H), 8.21 (d, 1H).

Example 6:

2-((1R, 3S) -3- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl Amino) cyclopentyl) acetic acid

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pterridin-10 (2H) -yl) acetaldehyde (step 1, of example 3) as starting material Produced by the method) and 2-((1R, 3S) -3-aminocyclopentyl) acetic acid using reductive amination using a procedure similar to Example 3.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.30 (m, 2H), 1.80 (m, 3H), 2.20 (m, 2H), 2.32 (d, 2H), 2.43 (s, 3H), 2.53 ( s, 3H), 3.00 (m, 1H), 3.65 (m, 2H), 4.92 (m, 2H), 7.78 (s, 1H), 7.98 (s, 1H), 8.65 (m, 1H), 11.48 (s , 1H), 12.14 (s, 1H).

Example 7:

(1R, 3R) -3- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethylamino) cyclo Pentanecarboxylic acid and 2,2,2-trifluoroacetic acid (1: 1)

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pterridin-10 (2H) -yl) acetaldehyde (step 1, of example 3) as starting material Produced by the method) and (1R, 3R) -3-aminocyclopentanecarboxylic acid by reductive amination using a procedure similar to Example 3.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.70 (m, 2H), 1.85 (m, 1H), 2.03 (m, 2H), 2.10 (m, 1H), 2.43 (s, 3H), 2.53 ( s, 3H), 2.90 (m, 2H), 3.73 (m, 2H), 4.92 (m, 2H), 7.78 (s, 1H), 7.98 (s, 1H), 8.66 (m, 2H), 11.49 (s , 1H), 12.35 (s, 1H).

Example 8:

7,8-dimethyl-10- (2-piperidin-1-yl-ethyl) -10H-benzo [g] pteridine-2,4-dione TFA salt

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde in methanol (20 mL) (step 1, implementation) Piperidine (40 μl, 0.4 mmol) and AcOH (0.5 mL) were added to a solution of the method (Example 3) (48 mg, 0.17 mmol) at room temperature. The reaction was stirred at 50 ° C. for 1 hour. The reaction was then cooled to room temperature and sodium cyanoborohydride (20 mg, 0.20 mmol) was added. After 17 hours, piperidine (0.1 mL) was added again and stirring was continued for 24 hours at room temperature. The solvent was removed in vacuo and the crude product was dissolved in DMSO / H ₂ O (1/7 mL), filtered and purified by preparative HPLC (Method 1). 8-dimethyl-10- (2-piperidin-1-yl-ethyl) -10H-benzo [g] pteridine-2,4-dione TFA salt (33 mg) was isolated after lyophilization of the appropriate fractions. (Yield 55%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.38 (m, 1H), 1.62 (m, 3H), 1.85 (m, 2H), 2.43 (s, 3H), 2.54 (s, 3H), 3.05 ( m, 2H), 3.49 (brs, 2H), 3.83 (m, 2H), 4.98 (m, 2H), 7.85 (s, 1H), 7.99 (s, 1H), 8.60 (brs, 1H) 11. 51 ( s, 1 H).

Example 9:

10- [2- (2-hydroxymethyl-pyrrolidin-1-yl) -ethyl] -7,8-dimethyl-10H-benzo [g] pteridine-2,4-dione

10- [2- (2-hydroxymethyl-pyrrolidin-1-yl) -ethyl] -7,8-dimethyl-10H-benzo [g] pteridine-2,4-dione (5 mg; yield : 3.8%) is 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde (using L-glutamic acid). Separation by preparative HPLC (method 1) as a byproduct of the reductive amination reaction of step 1, produced by the method of Example 3 (heating imine for 30 minutes at 40 ° C. instead of 3 hours at room temperature) However, see Example 3, Step 2 for preparation).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.57 (m, 1H), 1.90 (m, 1H), 2.03 (m, 1H), 2.17 (m, 1H), 2.41 (s, 3H), 3.54 ( m, 1H), 3.71 (m, 1H), 4.64 (m, 3H), 4.95 (m, 2H), 5.23 (m, 2H), 7.90 (s, 1H), 7.94 (s, 1H), 11.38 (s , 1H).

Example 10:

1- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetyl] -piperidine-4- Carboxylic acid

Step 1: Preparation of (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -acetic acid

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo in acetonitrile (2 mL), tert-butanol (8 mL) and methyl-1-cyclohexene (3 mL) [ g] Sodium chlorite in 2 ml of water at 0 ° C. in a suspension of pteridin-10 (2H) -yl) acetaldehyde (produced by the method of step 1, example 3) (50 mg, 0.18 mmol) 122 mg, 1.35 mmol) and sodium dihydrogen phosphate (148 mg, 1.23 mmol) were added dropwise over 5 minutes. After 2 hours, the reaction mixture was diluted with water and the organic layer was discarded. The aqueous phase was concentrated in vacuo and the resulting crude mixture was purified by preparative HPLC. (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetic acid (36 mg) was isolated after lyophilization of the appropriate fraction. (Yield 68%). LC-MS mlz 301.1 [M + H], retention time = 1.68 min.

Step 2: 1- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetyl] -piperidine Preparation of 4-carboxylic acid tert-butyl ester

(7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetic acid (50 mg, 0.17 mmol) in DMF (3 mL) And i-PrNEt ₂ (0.06 mL, 0.34 mmol) and HATU (65 mg, 0.17 mmol) were added sequentially to a suspension of piperidine-4-carboxylic acid tert-butyl ester (32 mg, 0.17 mmol) at room temperature. It was. After 17 hours, the temperature was raised to 50 ° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (3 mL) and purified using preparative HPLC purification (Method 1). 1- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetyl] -piperidine-4- Carboxylic acid tert-butyl ester (4.9 mg) was isolated after lyophilization of the appropriate fraction (yield: 7%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 5.63 (m, 2H), 4.08 (m, 2H), 2.88 ( m, 1H), 2.48 (s, 3H), 1.76 (m, 4H), 1.44 (s, 9H). LC-MS mlz 468.0 [M + H] ⁺ , retention time = 6.79 minutes.

Step 3: 1- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetyl] -piperidine Preparation of 4-carboxylic Acid

1- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] phthalin-10-yl)-in CH ₂ Cl ₂ (2 mL)- To a suspension of acetyl] -piperidine-4-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) was added trifluoroacetic acid (2 mL) at room temperature. After stirring for 2 hours, the reaction mixture was concentrated and the residual material was dissolved in water / acetonitrile and lyophilized. 1- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetyl] -piperidine-4- Carboxylic acid (7.2 mg) was isolated (yield: 80%). LC-MS mlz 410.1 [M ⁻ H] ⁻ , retention time = 4.99 min.

Example 11:

N- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] phthalin-10-yl) -ethyl] -2-methoxy-nicotine amides

Step 1: Preparation of 2-methoxy-nicotinic acid

2-methoxy-nicotinic acid methyl ester (500 mg, 3.0 mmol) was dissolved in methanol (5 mL) and water (1 mL). Sodium hydroxide (600 mg, 15 mmol) was added and the reaction mixture was refluxed for 2 hours. The solution was neutralized to pH 7 with 1N HCl and concentrated in vacuo. The solid was washed with 30 ml DCM / MeOH (1/1). The filtrate was concentrated in vacuo to give 2-methoxy-nicotinic acid (407 mg) as a white solid (yield: 88%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (m, 1H), 7.87 (m, 1H), 6.91 (m, 1H), 3.83 (s, 3H).

Step 2: N- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] phthalin-10-yl) -ethyl] -2-meth Preparation of oxy-nicotinamide

2-methoxy-nicotinic acid (20 mg, 0.12 mmol) and Hunig's base (0.024 mL, 0.14 mmol) were dissolved in DMF (1 mL), then HATU (53 mg, 0.14 mmol) was added at room temperature, 1 Stir for hours. 10- (2-amino-ethyl) -7,8-dimethyl-10H-benzo [g] pteridine-2,4-dione (39 mg, 0.14 mmol) (see intermediate 1 for the preparation) to DMF ( 1 ml) and added to the reaction mixture. After 3 hours, the reaction mixture was diluted with water (2 mL) and purification was performed using preparative HPLC (Method 3). 3- [2- (7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -ethylamino] -benzoic acid (12 mg) Was isolated after lyophilization of the appropriate fraction (yield: 24%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.37 (s, 1H), 8.48 (m, 1H), 8.28 (m, 1H), 8.02 (m, 1H), 7.89 (m, 2H), 4.81 ( m, 2H), 3.78 (m, 5H), 2.33 (s, 3H), 2.30 (s, 3H). LC-MS mlz 421.2 [M + H] ⁺ . Retention time = 5.31 minutes.

Example 12:

(S) -1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) -N- ( Methylsulfonyl) pyrrolidine-2-carboxamide

Methanesulfonamide was dissolved in DMF (3 mL) in (S) -1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridine-10 (2H). ) -Yl) ethyl) pyrrolidine-2-carboxylic acid [2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridine-10 (2H) Reductive amination using a similar procedure to Step 2, Example 3 using -yl) acetaldehyde (produced by the method of Step 1, Example 3) and (S) -pyrrolidine-2-carboxylic acid) Produced by (35 mg, 0.09 mmol), HATU (130 mg, 0.34 mmol) and DIPEA (0.2 mL, 1.14 mmol) at room temperature. The reaction was stirred for 1 hour. The solution was concentrated under reduced pressure, dissolved in ACN (6 mL) / water (2 mL) and purified by preparative HPLC (Method 2). Lyophilization (LCMS) of the combined pure fractions gave the desired product (6.1 mg, 14.5%) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.00 (m, 4H), 2.42 (s, 3H), 2.50 (s, 3H), 3.11 (s, 3H), 3.20 (m, 2H), 3.81 ( m, 1H), 4.16 (m, 1H), 4.87 (m, 1H), 4.99 (m, 1H), 7.76 (s, 1H), 7.96 (s, 1H), 11.45 (s, 1H).

Example 13:

(R) -1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) -N- ( Methylsulfonyl) pyrrolidine-2-carboxamide

Methanesulfonamide (74 mg, 0.77 mmol) was added (R) -1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] in DMF (8 mL). Putridin-10 (2H) -yl) ethyl) pyrrolidine-2-carboxylic acid [2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] prop Similar to Step 2, Example 3 using teridin-10 (2H) -yl) acetaldehyde (produced by the method of Step 1, Example 3) and (R) -pyrrolidine-2-carboxylic acid Produced by reductive amination using the procedure] (38 mg, 0.10 mmol), HATU (98 mg, 0.25 mmol) and diisopropylethylamine (100 mg, 0.77 mmol) were added at room temperature. The reaction was stirred for 1 hour. The solution was concentrated under reduced pressure, dissolved in ACN (6 mL) / water (2 mL) and purified by preparative HPLC (Method 2). The desired product (9.3 mg, 22.1%) by lyophilization (LCMS) of the combined pure fractions.

¹ H NMR (400 MHz, CD ₃ OD) δ 2.21 (m, 2H), 2.26 (m, 2H), 2.50 (s, 3H), 2.63 (s, 3H), 3.19 (s, 3H), 3.50 (m , 1H), 3.83 (m, 2H), 4.16 (m, 1H), 4.48 (m, 1H), 5.05 (m, 2H), 7.77 (s, 1H), 8.01 (s, 1H).

Example 14

7,8-dimethyl-10- [5- (2-oxo-1,2-dihydro-pyridin-3-ylamino) -pentyl] -10H-benzo [g] pteridine-2,4-dione

Step 1: Preparation of 5- (4,5-dimethyl-2-nitrophenylamino) pentan-1-ol

To a solution of 1-bromo-4,5-dimethyl-2-nitrobenzene (200 mg, 0.870 mmol) in anhydrous DMSO (1 mL) was added 5-aminopentan-1-ol (170 mg, 2.608 mmol). . The reaction mixture was heated in microwave at 140 ° C. for 20 minutes. The reaction mixture was concentrated in vacuo, diluted with water (5 mL) and the aqueous layer extracted with DCM (3 × 5 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The desired product (147 mg) was isolated (yield 67%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.55 (m, 2H), 1.66 (m, 2H), 1.79 (m, 2H), 2.20 (s, 3H), 2.29 (s, 3H), 2.38 (s, 2H), 3.32 (m, 2H), 3.71 (m, 2H), 6.64 (s, 1H), 7.95 (s, 1H).

Step 2: Preparation of 5- (2-amino-4,5-dimethylphenylamino) pentan-1-ol

Pd / C (8.4 mg) and sodium borohydride in a solution of 5- (4,5-dimethyl-2-nitrophenylamino) pentan-1-ol (147 mg, 0.583 mmol) in anhydrous MeOH (6 mL) under argon. (64 mg, 1.68 mmol) was added. Hydrogen was added using a balloon and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through celite, washed freely with EtOH and the solution was concentrated to give the crude product as a clear, colorless oil which was used for the next step.

Step 3: Preparation of 10- (5-hydroxypentyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

Crude 5- (2-amino-4,5-dimethylphenylamino) pentan-1-ol (0.583 mmol) was dissolved in glacial acetic acid (13 mL) under argon. Aloxane monohydrate (94 mg, 0.583 mmol) and boron oxide (81 mg, 1.165 mmol) were added to the stirring solution and the reaction was kept stirring at 25 ° C. for 2 hours under an argon atmosphere. The reaction mixture was evaporated in vacuo and the residue was added to dryness on silica gel using DCM as solvent and purified by Biotage flash column chromatography using gradient 0 to 10% MeOH in DCM as eluent. The desired product (70 mg) was isolated (yield 37%).

¹ H NMR (400 MHz, DMSO) δ 1.48 (m, 4H), 1.70 (m, 2H), 2.38 (s, 3H), 2.49 (s, 3H), 3.40 (m, 2H), 4.40 (t, 1H ), 4.55 (m, 2H), 7.78, (s, 1H), 7.88 (s, 1H), 11.28 (s, 1H). ESI (+) [M + Na] ⁺ = 351.2.

Step 4: Preparation of 10- (5-bromopentyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

10- (5-hydroxypentyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (72 mg, 0.219 mmol) and tetrabromide in anhydrous DMF (5 mL) Triphenyl phosphine (152 mg, 0.460 mmol) was added in portions to a solution of carbon (80 mg, 0.241 mmol) at 0 ° C. The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was added to dryness on silica gel using DCM: MeOH (50:50) as solvent and Biotage flash column chromatography using gradient 0 to 2% MeOH in DCM as eluent. Purification by chromatography. The desired product (60 mg) was isolated (yield: 70%).

¹ H NMR (400 MHz, DMSO) δ 1.60 (m, 2H), 1.73 (m, 2H), 1.90 (m, 2H), 2.40 (s, 3H), 2.50 (s, 3H), 3.58 (t, 2H ), 4.59 (m, 2H), 7.80 (s, 1H), 7.90 (s, 1H), 11.31 (s, 1H). ESI (+) m / z = 391.1, 393.1.

Step 5: 7,8-Dimethyl-10- [5- (2-oxo-1,2-dihydro-pyridin-3-ylamino) -pentyl] -10H-benzo [g] putridine-2,4 Dion

10- (5) in a suspension of 3-aminopyridin-2 (1H) -one (40 mg, 0.36 mmol) and Henig base (35 mg, 0.27 mmol) with catalytic amount of sodium iodide in anhydrous DMF (5 mL). -Bromopentyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (step 4 of this example) (70 mg, 0.18 mmol) was added at room temperature. The mixture is then heated to 80 ° C., stirred for 5 hours, concentrated (50 ° C.), dissolved in DMF / water (1/3), purified by preparative HPLC (method 1), isolated and lyophilized 7,8-dimethyl-10- [5- (2-oxo-1,2-dihydro-pyridin-3-ylamino) -pentyl] -10H-benzo [g] pteridine-2,4-dione ( 5 mg, yield: 6.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.52 (m, 2H), 1.64 (m, 2H), 1.76 (m, 2H), 2.08 (s, 3H), 3.04 (m, 2H), 4.59 ( m, 2H), 6.09 (m, 1H), 6.19 (m, 1H), 6.58 (m, 1H), 7.81 (s, 1H), 7.91 (s, 1H), 11.31 (s, 1H), 11.32 (brs ., 1H).

Example 15:

10- [5- (4-amino-2-oxo-2H-pyrimidin-1-yl) -pentyl] -7,8-dimethyl-10H-benzo [g] pteridine-2,4-dione

Sodium hydride was added to a suspension of 4-aminopyrimidin-2 (1H) -one (36 mg, 0.32 mmol) in anhydrous DMF (5 mL) cooled to 5 ° C. The reaction mixture was stirred at room temperature for 30 minutes and then 10- (5-bromopentyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (Example 14 (50 mg, 0.128 mmol) was added and the reaction mixture was stirred for 6 hours. The reaction mixture was concentrated (50 ° C.), dissolved in DMF / water (1/3), purified by preparative HPLC (method 1), isolated and lyophilized, and then 10- [5- (4-amino-2-oxo -2H-pyrimidin-1-yl) -pentyl] -7,8-dimethyl-10H-benzo [g] pteridin-2,4-dione (14 mg, yield: 26%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.46 (m, 2H), 1.74 (m, 4H), 2.40 (s, 3H), 2.51 (s, 3H), 3.78 (m, 2H), 4.57 ( m, 2H), 6.05 (d, 1H), 7.81 (s, 1H), 7.89 (s, 1H), 8.07 (d, 1H), 8.83 (s, 1H), 9.44 (s, 1H), 11.33 (s , 1H); LC-MS m / z 422.1 [M + H] ⁺

Example 16:

1- [2- (8-Chloro-7-methyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -ethyl] -piperidine- Preparation of 4-carboxylic Acid

Step 1: Preparation of 2- (5-chloro-4-methyl-2-nitro-phenylamino) -tetrahydro-pyran-3,4,5-triol

A solution of 5-chloro-4-methyl-2-nitro-phenylamine (19.8 g, 0.1 mol), ammonium chloride (0.1 g) and D-ribose (15.9 g, 0.1 mol) in EtOH (200 mL) was refluxed. , Stirred overnight. The reaction solution was concentrated under reduced pressure, resuspended in DCM: MeOH (1: 1) and the precipitated unreacted starting material was removed by filtration. The mother liquor was added to dryness on silica gel using DCM: MeOH (1: 1) and subjected to ISCO flash column chromatography. Use 100% DCM until the first peak is eluted, then elute 11.5 g of pure orange product as a sticky solid using 20% MeOH / DCM (yield: 40%) and 9.58 g of unreacted start The material was recovered. LC-MS mlz 318.7 [M + H], retention time 2.83 minutes. This crude material was used in the next step without further purification.

Step 2: Preparation of 5- (5-chloro-4-methyl-2-amino-phenylamino) -pentane-1,2,3,4-tetraol

Borohydride in a solution of 2- (5-chloro-4-methyl-2-nitro-phenylamino) -tetrahydro-pyran-3,4,5-triol (6.87 g, 0.02 mol) in EtOH (125 mL) Sodium (1.65 g, 0.043 mol) was added portionwise to control gas evolution so that the contents of the flask did not overflow. The resulting mixture was heated to reflux for 4 hours. The reaction mixture was then cooled to 0 ° C. at which time Pd / C (300 mg) was added along with additional sodium borohydride (1.65 g, 0.043 mol). Thereafter, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, washed freely with MeOH and finally concentrated to afford the crude product (as a clear purple oil) which was used directly in the next step. LC-MS: m / z 290.9 [M + H], retention time 1.38 minutes.

Step 3: Preparation of 8-Chloro-7-methyl-10- (2,3,4,5-tetrahydroxy-pentyl) -10H-benzo [g] pteridine-2,4-dione

Crude 5- (2-amino-5-chloro-4-methyl-phenylamino) -pentane-1,2,3,4-tetraol (0.022 mol) is dissolved in glacial acetic acid (80 ml), wrapped in foil and And stirred at room temperature. At this time, the flask was purged with argon for 20 minutes, and alloxan monohydrate (3.45 g, 0.022 mol) and boron oxide (1.35 g, 0.022 mol) were added to the stirring solution. The reaction was kept under argon atmosphere and stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure and the residue was dissolved in water (300 mL) and cooled in an ice bath. Then the precipitate was filtered off. The resulting filtrate was purified by preparative HPLC using Method 1 in 10 mL portions (30 injections). 8-chloro-7-methyl-10- (2,3,4,5-tetrahydroxy-pentyl) -10H-benzo [g] pteridine-2,4-dione (455 mg) was isolated after lyophilization. (Yield 5.3%). LC-MS mlz 397.1 [M + H], retention time 1.58 minutes.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.51 (s, 3H), 3.46 (m, 1H), 3.64 (m, 2H), 4.23 (m, 1H), 4.49 (m, 1H), 4.67 ( m, 1H), 4.78 (m, 2H), 4.88 (m, 1H), 5.15 (m, 2H), 8.13 (s, 1H), 8.20 (s, 1H), 11.47 (s, 1H).

Step 4: Preparation of (8-Chloro-7-methyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -acetaldehyde

8-Chloro-7-methyl-10- (2,3,4,5-tetrahydroxy-pentyl) -10H-benzo [g] prop in 2N aqueous sulfuric acid (60 mL) (in a silver foil flask) To a cooled (0 ° C.) suspension of terridine-2,4-dione (0.235 g, 0.0006 mol) was added (dropped) a solution of orthoiodic acid (0.41 g, 0.0018 mol) in water (25 mL). After 30 minutes, the reaction was allowed to warm to room temperature and stirred until a clear yellow solution. The pH of the reaction solution was carefully adjusted to 3.8-3.9 (using a pH meter) by the addition of solid sodium carbonate (it is important to carefully monitor the pH, otherwise the product will not precipitate out of solution if the pH exceeds 3.9). The precipitate was then filtered and washed freely with cold water, ethanol and diethyl ether to afford 0.089 g of the desired product as an orange solid (yield: 49%) LC-MS m / z 305.1 [M + H] retention Time: 1.69 min.

Step 5: 1- [2- (8-Chloro-7-methyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -ethyl] -p Preparation of Ferridine-4-carboxylic Acid

Piperidine-4-carboxylic acid (0.14 g, 0.0011 mol) was added to (8-chloro-7-methyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridine- 10-yl) -acetaldehyde (0.11 g, 0.0004 mol) and MeOH (10 mL) were added to a stirred mixture. The reaction mixture was heated to 40 ° C. and then 8 drops of glacial acetic acid were added. After 2 h NaCNBH ₃ (0.05 g, 0.0008 mol) was added to the reaction mixture and stirred at 40 ° C. for 23 h. The precipitate formed was separated by filtration to give an orange solid, which produced 0.061 g of the desired product (yield: 50%). LC-MS mlz 418.1 [M + H]; Retention time: 1.59 minutes.

Example 17:

1- [2- (8-Cyclopentylamino-7-methyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -ethyl] -piperi Preparation of Didine-4-carboxylic Acid

1- [2- (8-Chloro-7-methyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -ethyl in DMSO (5 mL) To a solution of] -piperidine-4-carboxylic acid (see Preparation of Example 16) (12 mg, 0.029 mmol) was added cyclopentylamine (12 mg, 0.15 mmol) at room temperature and the solution was 70 ° C. under argon. Stir at 20 h. Cyclopentylamine (0.1 mL, 1.36 mmol) was added and the mixture was stirred for an additional 8 hours. The reaction was cooled to room temperature, diluted with water (3 mL) and purified by preparative HPLC (Method 1). The desired product (9 mg) was obtained as a downy red solid after lyophilization of the appropriate fraction (yield: 69%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.75 (s, 1H), 6.6 (s, 1H), 5.05 (m, 3H), 4.32 (m, 1H), 3.7 (m, 2H), 3.5 (m , 1H), 2.37 (s, 3H), 2.3-2.08 (m, 8H), 1.90-1.78 (m, 8H); LC-MS mlz 467.2 (M + H), retention time 2.13 minutes.

Example 18:

1- (2- (3- (acetoxymethyl) -7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) Piperidine-4-carboxylic acid

Step 1: 1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-4 Preparation of Carboxylic Acids

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pterridin-10 (2H) -yl) acetaldehyde (step 1, of example 3) as starting material Produced by the process) and by piperidine-4-carboxylic acid using reductive amination using a procedure similar to step 5, Example 16.

Step 2: benzyl 1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine- Preparation of 4-carboxylate

1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-4-carboxyl A mixture of acid (224 mg, 0.56 mmol), benzyl chloride (4 mL, 34 mmol) and DIPEA (1.5 mL) was stirred at 60 ° C. for 3 days. The reaction was concentrated under reduced pressure, dissolved in water and washed with Et ₂ O (2 × 10 mL) to remove benzyl chloride. The product was extracted with chloroform (3 × 20 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated to afford 142 mg of crude product. This crude product was used for the next reaction without further purification. LC-MS mlz 488.0 [M + H] ⁺ , retention time 2.56 minutes.

Step 3: benzyl 1- (2- (3- (acetoxymethyl) -7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridine-10 (2H)- (1) Preparation of ethyl) piperidine-4-carboxylate

Benzyl 1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) pi in DMSO (5 mL) A mixture of ferridine-4-carboxylate (66 mg, 0.13 mmol), potassium carbonate (1.02 g, 7.3 mmol) and chloromethyl acetate (0.5 g, 4.6 mmol) was stirred at room temperature for 3 hours. Water was added to the reaction and the mixture was extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated to afford crude product. This crude product was used for the next reaction without further purification. LC-MS mlz 560.1 [M + H] ⁺ , retention time 2.89 minutes.

Step 4: 1- (2- (3- (acetoxymethyl) -7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl Preparation of ethyl) piperidine-4-carboxylic acid

Benzyl 1- (2- (3- (acetoxymethyl) -7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridine-10 () in MeOH (10 mL) A solution of 2H) -yl) ethyl) piperidine-4-carboxylate (0.13 mmol) and Pd / C (catalyst amount) was stirred for 1 hour at 1 atm under a hydrogen atmosphere. The mixture was filtered through a pad of celite. The filtrate was concentrated to dryness under reduced pressure. The crude product was dissolved in ACN (6 mL) / water (2 mL) and purified by preparative HPLC (Method 2). Lyophilization (LCMS) of the combined pure fractions gave 0.52 mg of the desired product as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.95 (m, 2H), 2.09 (s, 3H), 2.32 (m, 2H), 2.52 (s, 3H), 2.65 (s, 3H), 2.71 (m , 1H), 3.20 (m, 2H), 3.70 (m, 2H), 4.03 (m, 2H), 5.15 (m, 2H), 6.08 (s, 2H), 7.86 (s, 1H), 8.08 (s, 1H).

Example 19:

1- {2- [8- (2-tert-butoxycarbonyl-ethylamino) -7-methyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridine- Preparation of 10-yl] -ethyl} -piperidine-4-carboxylic acid

1- [2- (8-Chloro-7-methyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -ethyl in DMSO (6 mL) To a solution of] -piperidine-4-carboxylic acid (see Example 16 for preparation) (15 mg, 0.036 mmol) was added tert-butyl 3-aminopropanoate (0.1 mL, 1.3 mmol) at room temperature. The solution was stirred for 24 h at 70 ° C. under argon. The reaction was cooled to room temperature, diluted with water (3 mL) and purified by preparative HPLC (Method 1). The desired product (7.85 mg) was lyophilized and isolated as a downy red solid as TFA salt (yield: 41%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.6 (s, 1H), 11.13 (s, 1H), 8.8 (s, 1H), 7.75 (s, 1H), 7.2 (s, 1H), 6.6 ( s, 1H), 4.98 (m, 2H), 3.97 (m, 2H), 3.7 (m, 2H), 3.53 (bs, 3H), 3.01 (bs, 2H), 2.7 (t, 2H), 2.27 (s , 3H), 2.01 (m, 2H), 1.76 (BR, 2H), 1.41 (s, 9H); LC-MS mlz 527.1 (M + H), retention time 2.38 minutes.

Example 20:

(S) -1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) pyrrolidine- 2-carboxylic acid

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde in methanol (5 mL) (step 1, implementation) (S) -Pyrrolidine-2-carboxylic acid (20.3 mg, 0.176 mmol) and acetic acid (75 μl) were added to a solution of the method (Example 3) (50 mg, 0.176 mmol) at room temperature. The reaction was stirred at 50 ° C. for 30 minutes. The reaction was cooled to rt, sodium cyanoborohydride (25 mg, 0.39 mmol) was added and the reaction mixture was stirred at 50 ° C. for 24 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel) using gradient elution (DCM: MeOH: Et ₃ N 85: 14: 1 to 80: 19: 1) to give the desired product. (40.0 mg, 59% yield) was obtained.

¹ H NMR (400 MHz, DMSO) δ 1.75 (m, 3H), 1.99 (m, 1H), 2.39 (s, 3H), 2.59 (s, 3H), 2.62 (m, 1H), 2.88 (m, 1H ), 3.13 (m, 1H), 3.28 (m, 2H), 3.44 (bs, water), 4.71 (m, 2H), 7.82 (s, 1H), 7.86 (s, 1H), 11.32 (s, 1H) . ESI (−) m / z = 382.3.

Example 21:

Ethyl 1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-3-car Carboxylate

Ethyl 1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-3-car The carboxylates were prepared after 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde after the procedure described in Example 20. Synthesized by the method of Step 1, Example 3) (50 mg, 0.176 mmol) and ethyl piperidine-3-carboxylate (28 mg, 0.176 mmol). The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel) using isocratic elution (DCM: MeOH 97: 3) to afford the desired product (35.1 mg, 47% yield).

¹ H NMR (400 MHz, DMSO) δ 1.12 (t, 3H), 1.38 (m, 2H), 1.60 (m, 1H), 1.71 (m, 1H), 2.31 (m, 6H), 2.4 (s, 3H ), 2.74 (m, 3H), 2.94 (m, 1H), 3.97 (m, 2H), 4.70 (m, 2H), 7.76 (s, 1H), 7.88 (s, 1H), 11.30 (s, 1H) ; ESI (−) m / z = 426.4.

Example 22:

tert-butyl 1- (2- (2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-4-carboxylate

Step 1: Preparation of tert-butyl 1- (cyanomethyl) piperidine-4-carboxylate

To a solution of tert-butyl piperidine-4-carboxylate (750 mg, 4.05 mmol) in dry DCM (15 mL) 2-chloroacetonitrile (333 μl, 5.26 mmol) and potassium carbonate (1.7 g, 12.15 mmol ) Was added. The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with water (100 mL) and the aqueous layer was extracted with DCM (100 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was added to dryness on silica gel and purified by Biotage flash column chromatography using gradient 0 to 10% MeOH in DCM as eluent. The desired product (463 mg) was isolated (yield 51%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.44 (s, 9H), 1.73 (m, 2H), 1.93 (m, 2H), 2.19 (m, 1H), 2.35 (m, 2H), 2.79 (m, 2H), 3.51 (s, 2H).

Step 2: Preparation of tert-butyl 1- (2-aminoethyl) piperidine-4-carboxylate

Raney-nickel (catalyst amount) was added to a solution of tert-butyl 1- (cyanomethyl) piperidine-4-carboxylate (430 mg, 1.91 mmol) in EtOH (15 mL). The reaction mixture was placed at 50 psi H ₂ in a parr hydrogenator apparatus for 24 hours at room temperature. After the reaction was complete (monitored by TLC, 95: 5 DCM: MeOH), the mixture was filtered through a pad of celite and the pad was rinsed with ethanol. The filtrate was concentrated under reduced pressure and the resulting material was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.44 (s, 9H), 1.71 (2H), 1.88 (m, 2H), 2.22 (m, 3H), 2.69 (m, 2H), 2.84 (m, 2H) , 2.98 (m, 2 H), 3.53 (bs, 2 H).

Step 3: Preparation of tert-butyl 1- (2- (2-nitrophenylamino) ethyl) piperidine-4-carboxylate

To a solution of tert-butyl 1- (2-aminoethyl) piperidine-4-carboxylate (150 mg, 0.66 mmol) and sodium bicarbonate (110 mg, 1.31 mmol) in 2.5 mL DMF 2-fluorine under argon Ronnietrobenzene (77 μl, 0.72 mmol) was added. The reaction mixture was stirred at 70 ° C. for 18 hours. After the reaction was complete (monitored by TLC, hexanes: EtOAc, 4: 6), DMF was evaporated and the residue was dissolved in water (10 mL). The aqueous layer was extracted with EtOAc (20 mL) and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was added to dryness on silica gel and purified by Biotage flash column chromatography using gradient 0 to 60% EtOAc in hexane as eluent. Pure product (84 mg) was isolated (yield: 36%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.44 (s, 9H), 1.78 (m, 2H), 1.88 (m, 2H), 2.13 (m, 2H), 2.20 (m, 1H), 2.68 (m, 2H), 2.87 (m, 2H), 3.35 (m, 2H), 6.63 (t, 1H), 6.81 (d, 1H), 7.42 (t, 1H), 8.17 (d, 1H), 8.43 (bs, 1H ).

Step 4: Preparation of tert-butyl 1- (2- (2-aminophenylamino) ethyl) piperidine-4-carboxylate

Pd / C (8.4) under argon in a solution of tert-butyl 1- (2- (2-nitrophenylamino) ethyl) piperidine-4-carboxylate (84 mg, 0.24 mmol) in anhydrous MeOH (6 mL). Mg) and sodium borohydride (64 mg, 1.68 mmol) were added and the mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere (using a balloon). The reaction mixture was filtered through celite, washed freely with EtOH and the solution was concentrated to afford the crude product as a clear, colorless oil which was used directly in the next step.

Step 5: tert-Butyl 1- (2- (2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-4-carboxyl Rate

Crude tert-butyl 1- (2- (2-aminophenylamino) ethyl) piperidine-4-carboxylate (0.24 mmol) was dissolved in glacial acetic acid (6 mL) under argon. Aloxane monohydrate (39 mg, 0.24 mmol) and boron oxide (34 mg, 0.48 mmol) were added to the stirring solution and the reaction was kept stirring at 25 ° C. for 2 hours under an argon atmosphere. The residue was added to dryness on silica gel and purified by Biotage flash column chromatography using gradient 0 to 5% MeOH in DCM as eluent. The desired product (33 mg) was isolated (yield 32%).

¹ H NMR (400 MHz, DMSO) δ 1.38 (m, 10H), 1.72 (m, 2H), 2.11 (m, 3H), 2.48 (m, 1H), 2.64 (m, 2H), 2.88 (m, 2H ), 4.68 (m, 2H), 7.62 (m, 1H), 7.82 (m, 2H), 8.10 (m, 1H), 11.39 (s, 1H). ESI (+) m / z = 4.26.0.

Example 23:

1- (2- (2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-4-carboxylic acid trifluoroacetic acid

Tert-butyl 1- (2- (2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine- in anhydrous DCM (2 mL) To a solution of 4-carboxylate (see Example 22 for preparation) (23 mg, 0.053 mmol) was added TFA (200 μl, 2.58 mmol) and the mixture was stirred at 25 ° C. for 16 h. The solution was concentrated under reduced pressure, and the residue was dissolved in DMSO (1 mL), filtered and purified by preparative HPLC (Method 1). The desired product (12.7 mg) was isolated after lyophilization (yield: 48.8%).

¹ H NMR (400 MHz, DMSO) δ 1.78 (m, 2H), 2.06 (m, 2H), 3.09 (m, 3H), 3.44 (m, 2H), 3.89 (m, 2H), 4.99 (m, 2H ), 7.68 (m, 1H), 7.97 (m, 1H), 8.06 (m, 1H), 8.17 (m, 1H), 9.43 (bs, 1H), 11.60 (s, 1H), 12.61 (bs, 1H) . ESI (+) m / z = 370.0.

For Examples 24, 25 and 26, the following analytical HPLC method was used.

From Agilent 1100 HPLC, Agilent XDB C ₁₈ 50 × 4.6 mm 1.8 micron column, 1.5 ml / min, solvent A-water (0.1% TFA), solvent B-acetonitrile (0.07% TFA), gradient-5 min from 95% A 95% B; Hold for 1 minute; Then recycle, UV detection about 214 and 254 nm.

For Examples 25 and 26, the following preparative reverse phase chromatography method was used: Varian PrepStar, Phenomenex Luna (2) C ₁₈ 250 × 21.2 mm 10 micron column, 20 mL / min, solvent B-water (0.1% TFA ), Solvent A-acetonitrile (0.07% TFA), gradient-10 min 80% A from 5% A; 100% A from 5% 80% A; Keep 5 minutes; Then recycle, UV detection about 254 nm.

Example 24:

Ethyl 1- [2- (8-chloro-7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl] piperidine-4 Carboxylate

Step 1: Preparation of ethyl 1- {2-[(5-chloro-4-methyl-2-nitrophenyl) amino] ethyl} piperidine-4-carboxylate

1,8-diazabicyclo [5.4.0] undec-7-ene (1.2 mL, 7.8 mmol) was dissolved in 1,5-dichloro-2-methyl-4-nitrobenzene (0.81 g, in DMSO (7.8 mL), 3.9 mmol) and ethyl 1- (2-aminoethyl) piperidine-4-carboxylate (1.6 g, 7.8 mmol) were added and the red solution was stirred at 100 ° C. under a nitrogen atmosphere. After 3.5 h it was taken up in ethyl acetate / hexanes and the organic layer was washed with water followed by brine. It was dried using sodium sulfate, filtered and concentrated in vacuo. The brown residue was purified by silica gel flash chromatography eluting with 15%, 20% and 25% ethyl acetate / hexanes to give 0.66 g of the desired product in vacuo and then as an amorphous orange solid (yield: 45.7%). Mass spectrum (ESI ⁺ ) for C ₁₇ H ₂₄ ClN ₃ O ₄ m / z 370.0 (M + H) ⁺ . HPLC retention time 3.29 minutes. (System D).

Step 2: Preparation of ethyl 1- {2-[(2-amino-5-chloro-4-methylphenyl) amino] ethyl} piperidine-4-carboxylate

Raney nickel (50 mg, 0.85 mmol) and ethyl 1- {2-[(5-chloro-4-methyl-2-nitrophenyl) amino] ethyl} piperidine-4-carboxylate in ethanol (20 mL) (0.66 g, 1.79 mmol) of the well stirred slurry was alternately emptied and then charged with 1 atmosphere of hydrogen (three times) (balloon). After 3 h at rt, the mixture was filtered through Celite ^® and concentrated in vacuo to afford the desired product as a brown oil. 0.59 g (99% yield). Mass spectrum (ESI ⁺ ) for C ₁₇ H ₂₆ ClN ₃ O ₂ m / z 340.1 (M + H) ⁺ . HPLC retention time 2.53 minutes. (System D).

Step 3: Ethyl 1- [2- (8-chloro-7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl] piperi Preparation of Didine-4-carboxylate

Ethyl 1- {2-[(2-amino-5-chloro-4-methylphenyl) amino] ethyl} piperidine-4-carboxylate (56 mg, 0.16 mmol) in acetic acid (2 mL), aloxylyl A mixture of hydrate (26.4 mg, 0.165 mmol) and boric acid (20.4 mg, 0.330 mmol) was stirred at room temperature under nitrogen and wrapped in tinfoil. After 16 h, concentrated in vacuo to give a brown oil, which was stirred rapidly for 1 h as a suspension with saturated aqueous sodium bicarbonate and ethyl acetate (10 mL each). The precipitate was filtered off, rinsed with ethyl acetate and diethyl ether and air dried to give 58 mg (yield: 79%) of the desired product.

¹ H NMR (400 MHz, CD3CN) δ 1.22 (3 H, t), 1.57 (2 H, m), 1.82 (2 H, m), 2.22 (3 H, m), 2.54 (3 H, s), 2.76 (2 H, m), 2.93 (2 H, m), 4.09 (2 H), 4.68 (2 H, m), 7.98 (1 H, s), 8.06 (1 H, s), 9.27 (1 H , br s). Mass spectrum (ESI ⁺ ) for C ₂₁ H ₂₄ ClN ₅ O ₄ m / z 446.0 (M + H) ⁺ . HPLC retention time 2.44 minutes. (System D).

Example 25:

1- [2- (8-amino-7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10- (2H) -yl) ethyl] piperidine-4 -Carboxylic acid

Step 1: 1- [2- (8-benzylamino-7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl] piperi Preparation of Didine-4-carboxylic Acid Acetate

Benzylamine (98.0 μl, 0.90 mmol) and ethyl 1- [2- (8-chloro-7-methyl-2,4-dioxo-3,4-dihydro in N, N-dimethylacetamide (1 mL) A mixture of benzo [g] pteridin-10 (2H) -yl) ethyl] piperidine-4-carboxylate (40.0 mg, 0.090 mmol) was heated at 80 ° C. for 19 hours. Tetrahydrofuran (3.8 mL, 47 mmol) and lithium hydroxide (1 M aqueous, 0.9 mL) were added to the crude material and stirred at room temperature. After 1 h, the mixture was concentrated in vacuo to give a red oil. Celite ^® was added and 100 mL methanol was added. The mixture is dried in vacuo and the Celite ^® mixture is added onto a 28x55 mm C-18 reversed phase silica gel column (18.4 g), followed by 2% acetic acid / water and (5% to 20% acetonitrile + 5% acetic acid) Eluted with water. The appropriate fractions were concentrated in vacuo to give 43.2 mg of the desired product as an amorphous red solid (yield: 87%). Mass spectrum (ESI ⁺ ) for C ₂₆ H ₂₈ N ₆ O ₄ m / z 489.0 (M + H) ⁺ . HPLC retention time 2.29 minutes. (System D).

Step 2: 1- [2- (8-Amino-7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10- (2H) -yl) ethyl] piperi Preparation of Didine-4-carboxylic Acid Acetate

1- [2- (8-benzylamino-7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl] piperidine-4 Carboxylic acid (30.6 mg, 0.056 mmol) was dissolved in water (4.0 mL) and acetic acid (0.4 mL) and 10% palladium on carbon (2 mg) was added. The rapidly stirred mixture was discharged alternately and then filled with 1 atmosphere of hydrogen (three times) (balloon). After 2 h the mixture was filtered, rinsed with 5% acetic acid in water and concentrated in vacuo. The red residue was subjected to flash chromatography on a column of C-18 reversed silica gel (28 mm diameter, 13.5 g) and eluted with water, 5% acetic acid / water and (5% acetonitrile + 5% acetic acid) / water. The desired product was obtained as an amorphous red solid, 16.5 mg. (Yield 64%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.06 (br s, 1 H), 10.94 (s, 1 H), 7.66 (s, 1 H), 7.27 (s, 2 H), 6.76 (s, 1 H), 4.35 (m, 2 H), 2.94 (m, 2 H), 2.62 (m, 2 H), 2.23 (s, 3 H), 2.16 (m, 3 H), 1.91 (s, 3 H ), 1.80 (m, 2H), 1.53 (m, 2H).

Mass spectrum (ESI ⁺ ) for C ₁₉ H ₂₂ N ₆ O ₄ m / z 399.0 (M + H) ⁺ . HPLC retention time 1.69 min. (System D).

Example 26:

1- [2- (8-dimethylamino-7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10- (2H) -yl) ethyl] piperidine- 4-carboxylic acid

N, N-dimethylformamide (0.2 mL) and dimethylamine (0.3 mL, 2M in THF) were added to ethyl 1- [2- (8-chloro-7-methyl-2,4-dioxo-3,4-di To hydrobenzo [g] pteridin-10 (2H) -yl) ethyl] piperidine-4-carboxylate (25.0 mg, 0.0561 mmol) and the mixture was heated at 80 ° C. for 1 hour. Dry blow under nitrogen flow gave a dark red residue. THF (2.4 mL) and lithium hydroxide (0.6 mL, 1M aqueous) were added and the mixture was stirred at rt for 1 h. Glacial acetic acid (0.345 mL) was added and the solvent was removed in vacuo. The residue was dissolved in water (7 mL) and the red solution was chromatographed on a 28 × 80 mm column of C-18 reversed phase silica gel. Elution used water, 25% methanol / water and 45% methanol / water. The appropriate fractions were concentrated in vacuo to give 15.9 mg of the desired product as an amorphous red solid (yield: 66%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (br s, 1 H), 7.78 (s, 1 H), 6.98 (s, 1 H), 4.69 (m, 2 H), 3.06 (s, 6 H), 2.92 (m, 2 H), 2.64 (m, 2 H), 2.45 (s, 3 H), 2.09 (m, 2 H), 1.96 (m, 1 H), 1.72 (m, 2 H ), 1.45 (m, 2H). Mass spectrum (ESI ⁺ ) for C ₂₁ H ₂₆ N ₆ O ₄ m / z 427.0 (M + H). HPLC retention time 2.00 min (System D).

Example 27

1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-4-carboxyl Manufacture of acid

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pterridin-10 (2H) -yl) acetaldehyde (step 1, of example 3) as starting material Produced by the process) and by piperidine-4-carboxylic acid using reductive amination using a procedure similar to step 5, Example 16.

Example 28

7,8-dimethyl-10- [5- (2-oxo-2H-pyrimidin-1-yl) -pentyl] -10H-benzo [g] pteridine-2,4-dione

To a suspension of pyrimidin-2 (1H) -one hydrochloride (100 mg, 0.755 mmol) and potassium carbonate (104 mg, 0.755 mmol) in anhydrous DMF (5 mL) 10- (5-bromopentyl) -7,8 -Dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (see step 4 of Example 14 for preparation) (50 mg, 0.128 mmol) was added at room temperature. The mixture was heated to 50 ° C., stirred for 8 hours, concentrated (50 ° C.), dissolved in DMF / water (1/3) and purified by preparative HPLC (method 1) to give the following after lyophilization.

7,8-dimethyl-10- [5- (2-oxo-2H-pyrimidin-1-yl) -pentyl] -10H-benzo [g] pteridine-2,4-dione (I) (10.9 mg , Yield: 21%)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.45 (m, 2H), 1.76 (m, 4H), 2.39 (s, 3H), 2.51 (s, 3H), 3.95 (m, 2H), 4.57 ( m, 2H), 6.58 (dd, 1H), 7.83 (s, 1H), 7.90 (s, 1H), 8.50 (dd, 1H), 8.61 (m, 1H), 11.31 (s, 1H); LC-MS mlz 407.1 [M + H] ⁺ and

7,8-dimethyl-10- [5- (pyrimidin-2-yloxy) -pentyl] -10H-benzo [g] pteridine-2,4-dione (II) (4 mg, yield: 7.7% )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.59 (m, 2H), 1.81 (m, 4H), 2.40 (s, 3H), 4.32 (m, 2H), 4.61 (m, 2H), 7.12 ( m, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.58 (d, 2H), 11.30 (s, 1H).

Using the methods described above and selecting the appropriate starting materials, other compounds of the invention were produced and characterized. These compounds together with the examples described above are summarized in Table 1 below.

Example 29

10- (2- (4- (aminomethyl) piperidin-1-yl) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione bis (2, 2,2-trifluoroacetate)

<Scheme 1>

Step 1: Preparation of 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde

To a suspension of riboflavin (8.5 g, 0.0023 mol) in 2 N aqueous sulfuric acid (225 ml) cooled to 0 ° C. in a flask wrapped with tinfoil, add orthoguadioic acid (18.9 g, 0.0825 mmol) and add to water (200 ml) Dissolved. After 30 minutes, the reaction was allowed to warm to room temperature. Once the reaction mixture became clear (clear, yellow solution), the sodium carbonate was added to carefully adjust the pH of the reaction solution to 3.8-3.9 (using a pH meter). (It is important to carefully monitor the pH, if the pH is above 3.9 the product will not precipitate out of solution). The precipitate was then separated by filtration and washed freely with cold water, ethanol and diethyl ether to afford the desired product (6.04 g, 94%) as an orange solid. LC-MS mlz 285.1 [M + H] ⁺ , retention time 1.63 minutes.

Step 2: tert-butyl ((1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) Preparation of Piperidin-4-yl) methyl) carbamate

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetaldehyde (100 mg, in MeOH (15 mL) To a suspension of 0.352 mmol) tert-butyl (piperidin-4-ylmethyl) carbamate (226 mg, 1.056 mmol) and AcOH (0.1 mL) were added respectively and stirred at room temperature for 2 hours. Then NaCNBH ₃ (66 mg, 1.056 mmol) was added to the reaction mixture and stirred at rt for 24 h. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 2). The combined fractions were lyophilized to give the desired product tert-butyl ((1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridine-10 (2H) ) -Yl) ethyl) piperidin-4-yl) methyl) carbamate (104 mg, 62%) was obtained as a pale yellow solid.

¹ H NMR (400 MHz, MeOH-d4): δ 1.46 (s, 9H), 1.61 (m, 2H), 1.84 (m, 1H), 2.04 (d, 2H), 2.51 (s, 3H), 2.63 ( s, 3H), 3.03 (d, 2H), 3.13 (t, 2H), 3.68 (t, 2H), 3.97 (d, 2H), 5.12 (t, 2H), 7.82 (s, 1H), 8.03 (s , 1H). LC-MS mlz 483.1 (M + H) ⁺ , retention time: 2.40 minutes (method A).

Step 3: 10- (2- (4- (aminomethyl) piperidin-1-yl) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione bis Preparation of (2,2,2-trifluoroacetate)

Tert-butyl benzyl (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) in DCM (2 mL) To a solution of carbamate (96 mg, 0.2 mmol) was added TFA (2 mL). The reaction mixture was stirred at rt for 2 h. After 2 hours, the reaction mixture was concentrated and the residual material was dissolved in MeOH (10 mL) and purified by preparative HPLC (Method 2). The combined fractions were lyophilized to give the desired product 10- [2- (4-aminomethyl-piperidin-1-yl) -ethyl] -7,8-dimethyl-10H-benzo [g] pteridine-2, 4-Dione di-trifluoroacetic acid salt (52 mg, 68%) was obtained as a pale yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.38 (m, 2H), 1.96 (m, 1H), 2.0 (d, 2H), 2.43 (s, 3H), 2.53 (s, 3H), 2.76 (m, 2H), 3.09 (t, 2H), 3.68 (t, 2H), 3.97 (d, 2H), 5.00 (t, 2H), 7.86 (s, 1H), 7.95 (m, 4H), 9.14 ( br s, 1 H), 11.47 (br s, 1 H).

Example 30

N-cyano-1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine -4-carboxamide

<Reaction Scheme 2>

1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-4-carboxyl Acid (10 mg, 0.0254 mmol) (using the method of Example 29, step 2 and as starting material 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo) [g] pteridin-10-yl) -produced using acetaldehyde and piperidine-4-carboxylic acid), DMAP (3.1 mg, 0.0254 mmol) and cyanamide (21 mg, 0.05 mmol) It was dissolved in anhydrous DMF (1 mL). HATU (11.5 mg, 0.03 mmol) was added to the reaction mixture. The mixture was stirred for 24 h at 20 ° C., diluted with water (2 mL) and then purified by preparative HPLC (Method 1). N-cyano-1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine 4-Carboxamide was isolated in 46% (6 mg) yield. LC-MS mlz 422.0 [M + H] &lt; + &gt;, retention time 1.66 minutes.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.76 (m, 2H), 2.05 (m, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 2.60 (m, 1H), 3.05 ( m, 2H), 3.49 (s, 2H), 3.90 (m, 2H), 4.96 (s, 2H), 7.97 (s, 1H), 7.99 (s, 1H), 9.35 (br s, 1H), 11.48 ( s, 1 H).

Example 31

N- (1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperidine-4 -Yl) methanesulfonamide 2,2,2-trifluoroacetate

<Reaction Scheme 3>

Step 1: 10- (2- (4-Aminopiperidin-1-yl) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione bis (2, 2,2-trifluoroacetate)

10- (2- (4-aminopiperidin-1-yl) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione was prepared by the procedure of Example 29. And (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -acetaldehyde (102 mg, 0.36 mmol) and blood Synthesis in 88% yield using ferridin-4-amine (216 mg, 1.08 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.73 (br m, 2H), 2.12 (br m, 2H), 2.43 (s, 3H), 2.53 (s, 3H), 3.17 (br m, 2H) , 3.32 (br m, 2H), 3.54 (m, 1H), 3.99 (br m, 2H), 4.98 (bt, 2H), 7.86 (s, 1H), 7.98 (s, 1H), 8.14 (br s, 3H), 8.95 (br s, 1 H), 11.50 (s, 1 H).

Step 2: N- (1- (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) piperi Dyn-4-yl) methanesulfonamide 2,2,2-trifluoroacetate

10- (2- (4-aminopiperidin-1-yl) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione in anhydrous DMF (3 mL) To 32 ° C., 0.087 mmol) was added dropwise methanesulfonyl chloride (0.1 mL) under an argon atmosphere. Trimethylamine (0.1 mL) was then added to the reaction mixture to become cloudy. The reaction mixture was stirred at 0 ° C. for 1.25 h, then warmed to rt and stirred for 3.25 h. The crude reaction mixture was diluted with water (7 mL) and purified by preparative HPLC (Method 4). The desired fractions were combined, lyophilized and the desired product was obtained in 24% (12 mg) yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.63 (q, 2H), 1.94 (br s, 1H), 2.10 (d, 2H), 2.43 (s, 3H), 2.54 (s, 3H), 2.97 (s , 3H), 3.51 (br s, 4H), 3.93 (br m, 2H), 4.98 (br s, 2H), 7.37 (m, 1H), 7.84 (s, 1H), 7.99 (s, 1H), 8.54 (br m, 1 H), 11.52 (s, 1 H).

Example 32

(S) -10- (2- (2- (2H-tetrazol-5-yl) pyrrolidin-1-yl) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 ( 3H, 10H) -dione

<Reaction Scheme 4>

Step 1: Preparation of (S) -5- (pyrrolidin-2-yl) -2H-tetrazole

(S) -pyrrolidine-2-carbonitrile hydrochloride (250 mg, 1.88 mmol) and dibutyl tin oxide (140 mg, 0.56 mmol) were suspended in dioxane (10 mL) and azidotrimethyl silane (0.9 mL) , 7.52 mmol) was added to the mixture under Ar. The resulting mixture was heated to 110 ° C. for 21 hours. Dibutyltin oxide (140 mg, 0.56 mmol) and azidotrimethyl silane (0.9 mL, 7.52 mmol) were added and heating was continued at 110 ° C. for another 21 hours. Solvent was removed by evaporation and (S) -10- (2- (2- (2H-tetrazol-5-yl) pyrrolidin-1-yl) without further purification of the crude product (207 mg). Ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione was used for the synthesis.

Step 2: (S) -10- (2- (2- (2H-tetrazol-5-yl) pyrrolidin-1-yl) ethyl) -7,8-dimethylbenzo [g] pteridine-2 Of 4,3H, 10H) -dione

The title compound was used in the procedure of Example 29, step 2 in 14% (14.5 mg) yield, and 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] prop Teridin-10 (2H) -yl) acetaldehyde (77 mg, 0.27 mmol) and (S) -5- (pyrrolidin-2-yl) -2H-tetrazole (207 mg, crude) as starting material Produced using.

¹ H NMR (400 MHz, CD ₃ OD) δ 2.40 (m, 2H), 2.42 (s, 3H), 2.52 (m, 1H), 2.54 (s, 3H), 2.61 (m, 1H), 3.75 (br m, 2H), 3.95 (br m, 1H), 4.07 (br m, 1H), 5.09 (br m, 2H), 5.34 (br m, 1H), 7.77 (s, 1H), 7.89 (s, 1H) .

Example 33

10- (2-((2- (1,1-dioxido-3-oxo-1,2,5-tiodiazolidin-2-yl) ethyl) amino) ethyl) -7,8-dimethylbenzo Preparation of [g] pteridine-2,4 (3H, 10H) -dione

Scheme 5

Step 1: Preparation of ethyl 2-((N- (tert-butoxycarbonyl) sulfamoyl) amino) acetate

2-Methylpropan-2-ol (1.07 g, 14.4 mmol) was added to a solution of sulfur isocyanate chloride (2.06 g, 14.5 mmol) in anhydrous DCM (50 mL) at 0 ° C. The reaction mixture was allowed to warm to rt, stirred for 10 min and then cooled to 0 ° C. To this mixture was added a solution of ethyl 2-aminoacetate hydrochloride (2.03 g, 14.5 mmol) and triethylamine (1.42 g, 14 mmol) in 30 mL of DCM, followed by triethylamine (1.93 g, 19 mmol). Added. The resulting mixture was stirred for 1 hour at room temperature, 0.1N HCl (20 mL) was added and separated into two layers. The organic layer was washed with H ₂ O (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by BIOTAGE flash column chromatography using gradient 0 to 100% EtOAc in DCM as eluent. The desired product was isolated in 55% (2.3 g) yield.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ 1.32 (t, 3H), 1.52 (s, 9H), 3.98 (d, 2H), 4.25 (q, 2H), 5.68 (t, 1H), 7.31 ( s, 1 H).

Step 2: Preparation of ethyl 2-((N- (2-(((benzyloxy) carbonyl) amino) ethyl) -N- (tert butoxycarbonyl) sulfamoyl) amino) acetate

Ethyl 2-((N- (tert-butoxycarbonyl) sulfamoyl) amino) acetate (616 mg, 2.18 mmol), benzyl (2-hydroxyethyl) carbamate (678 mg, 3.47 mmol), DIAD ( 478 mg, 2.36 mmol) and triphenylphosphine (590 mg, 2.24 mmol) were stirred in THF for 1 hour at room temperature. The solvent was evaporated and the residue was purified by BIOTAGE flash column chromatography using 100% EtOAc from gradient 0 in DCM as eluent. The desired product was isolated as pale yellow oil (820 mg, 82%). ESI (+) [M + H] ⁺ = 459.7.

Step 3: Preparation of ethyl 2-((N- (2-(((benzyloxy) carbonyl) amino) ethyl) sulfamoyl) amino) acetate

Ethyl 2-((N- (2-(((benzyloxy) carbonyl) amino) ethyl) -N- (tert-butoxycarbonyl) sulfamoyl) amino) acetate in DCM (2 mL) (820 mg, 1.78 mmol) and TFA (6 mL) were stirred at rt for 30 min. The solvent was reduced in vacuo and the crude product was dissolved in EtOAc (100 mL), washed with saturated aqueous NaHCO ₃ (20 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford Obtained as a pale yellow solid (618 mg, 96%). This compound was used in the next step without further purification.

Step 4: Preparation of benzyl (2- (1,1-dioxido-3-oxo-1,2,5-thiadiazolidin-2-yl) ethyl) carbamate

Ethyl 2-((N- (2-(((benzyloxy) carbonyl) amino) ethyl) sulfamoyl) amino) acetate (528 mg, 1.46 mmol) and K ₂ CO ₃ (3.4 in anhydrous DMSO (5 mL) g, 24.6 mmol) was stirred overnight at 40 ° C. EtOAc (200 mL) was added to the reaction mixture at room temperature and the solids were removed by filtration. The filtrate was washed with saturated aqueous NaHCO ₃ (50 mL) followed by brine (50 mL × 2). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the product as a pale yellow solid (310 mg, 67%). This compound was used without further purification.

Step 5: Preparation of 2- (2-aminoethyl) -1,2,5-thiadiazolidin-3-one 1,1-dioxide hydrochloride

Benzyl (2- (1,1-dioxido-3-oxo-1,2,5-thiadiazolidin-2-yl) ethyl) carbamate (56 mg, 0.17 mmol) in methanol (5 mL) The solution of was purged with argon for 10 minutes. 4N HCl / dioxane (0.05 mL, 0.2 mmol) was then added, palladium on carbon was added and the reaction mixture was left under hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved again in MeOH (0.5 mL). Hexane was added to precipitate the desired product which was filtered to give 2- (2-aminoethyl) -1,2,5-thiadiazolidin-3-one 1,1-dioxide hydrochloride (33 mg, 86%) Got.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.02 (t, 2H), 3.36 (s, 1H), 3.80 (t, 2H), 4.09 (s, 2H), 8.38 (s, 3H).

Step 6: 10- (2-((2- (1,1-dioxido-3-oxo-1,2,5-thiadiazolidin-2-yl) ethyl) amino) ethyl) -7,8 Preparation of -dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetate

2- (2-aminoethyl) -1,2,5-thiadiazolidin-3-one 1,1-dioxide hydrochloride (23 mg, 0.10 mmol), 2- (7,8 in MeOH (5 mL) A mixture of dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde (23 mg, 0.08 mmol) and two drops of acetic acid was heated to 40 ° C. Stirred for 40 min. To this solution was added NaCNBH ₃ (27 mg, 0.42 mmol) and the mixture was stirred overnight. The mixture was concentrated and the residue was dissolved in water (3 mL) -DMF (2 mL) and purified by preparative HPLC (method 2).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.41 (s, 3H), 2.50 (s, 3H), 3.00 (m, 2H), 3.56 (d, 2H), 3.63 (m, 2H), 3.72 ( s, 2H), 4.76 (m, 2H), 7.34 (m, 1H), 7.66 (m, 1H), 7.91 (s, 2H), 11.37 (s, 1H). ESI (+) [M + H] ⁺ = 448.0.

Example 34

10-((1-benzylpiperidin-2-yl) methyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

<Reaction Scheme 6>

Step 1: Preparation of (1-benzylpiperidin-2-yl) methanol

(1-benzylpiperidin-2-yl) methanol was produced by stirring piperidin-2-ylmethanol (1.16 g, 10 mmol) in acetonitrile (50 mL) at room temperature. Benzyl bromide (1.88 g, 11 mmol) and diisopropylethylamine (2.60 g, 20 mmol) were added in one portion and the resulting solution was stirred at room temperature for 2 hours. The mixture was then evaporated under reduced pressure. DCM (50 mL) was added and washed sequentially with saturated aqueous NaHCO ₃ (50 mL) and 1 M KOH (10 mL). The aqueous phase was extracted with DCM (25 mL) and the combined organic portions were dried over Na ₂ SO ₄ , filtered and evaporated to give 2.02 g (9.86 mmol, 99% yield) of the desired product as a yellow oil. LC-MS mlz 206.1 [M + H] ⁺ , retention time 3.22 minutes.

Step 2: Preparation of (1-benzylpiperidin-2-yl) methyl methanesulfonate

(1-benzylpiperidin-2-yl) methyl methanesulfonate was prepared by stirring (1-benzylpiperidin-2-yl) methanol (2.02 g, 9.86 mmol) at 0 ° C. in DCM (50 mL). Methanesulfonyl chloride (1.55 mL, 20.0 mmol) was added dropwise over 2.5 minutes, followed by triethylamine (2.65 mL, 20 mmol) dropwise over 5 minutes. The reaction mixture was allowed to warm to room temperature with stirring over 165 minutes. The reaction mixture was poured into DCM (25 mL) and H ₂ O (75 mL), and then the organic phase was washed sequentially with saturated aqueous NH ₄ Cl (25 mL) and brine (40 mL), then dried over Na ₂ SO ₄ . , Filtered and evaporated to afford the desired product (2.77 g, 99% yield) as an orange-yellow oil which was used in the next step without further purification.

Step 3: Preparation of N-((1-benzylpiperidin-2-yl) methyl) -4,5-dimethyl-2-nitroaniline

To a solution of 4,5-dimethyl-2-nitroaniline (0.91 g, 5.5 mmol) in DMF (25 mL) was added sodium hydride (132 mg, 5.5 mmol) over 3 minutes at room temperature under Ar. The resulting solution was stirred at room temperature for 10 minutes, and then (1-benzylpiperidin-2-yl) methyl methanesulfonate (1.41 g, 5.0 mmol) was added in one portion at room temperature. The reaction mixture was stirred for 18 h at room temperature under Ar. Water (50 mL) was added and the mixture was poured into DCM (200 mL) and H ₂ O (400 mL). The organic phase was washed sequentially with H ₂ O (2 × 200 mL) and brine (150 mL), dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is then purified by column chromatography (0-100% EtOAc in hexanes) to give N-((1-benzylpiperidin-2-yl) methyl) -4,5-dimethyl-2-nitroaniline (480 mg, 27%) was obtained as a dark red solid. LC-MS mlz 354.1 [M + H] ⁺ , retention time 5.03 minutes.

Step 4: N ^One Preparation of-((1-benzylpiperidin-2-yl) methyl) -4,5-dimethylbenzene-1,2-diamine

N-((1-benzylpiperidin-2-yl) methyl) -4,5-dimethyl-2-nitroaniline (480 mg, 1.36 mmol) was dissolved in MeOH (25 mL). The reaction vessel was placed under vacuum and then repressurized with Ar and the process was repeated. Pd / C (10% Pd / C, 3% Pd w / w) was added to the solution and the mixture was cooled to 0 ° C. under Ar. NaBH ₄ (216 mg, 5.7 mmol) was added in portions over 10 minutes at 0 ° C., then the reaction was stirred at 0 ° C. for 1 hour, at which time the reaction mixture was poured into celite using MeOH (50 mL). Filtration elutes the product. The solvent is then evaporated to give 766 mg (quantitative) of N ¹ -((1-benzylpiperidin-2-yl) methyl) -4,5-dimethylbenzene-1,2-diamine as a mixture of borates, which is It was used for the next step without further purification.

Step 5: Preparation of 10-((1-benzylpiperidin-2-yl) methyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

Crude N ¹ -((1-benzylpiperidin-2-yl) methyl) -4,5-dimethylbenzene-1,2-diamine (1.36 mmol), siloxane monohydrate (229 mg, 1.43 mmol) and Boric acid (168 mg, 2.72 mmol) was dissolved in AcOH (15 mL) at room temperature and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then evaporated to dryness, dissolved in DCM (50 mL), H ₂ O (45 mL) was added, and the aqueous phase extracted with DCM (2 × 20 mL). The combined organic portions were washed with brine (75 mL), dried over Na ₂ SO ₄ , filtered and evaporated to give a solid which was purified by column chromatography (0% to 15% MeOH in DCM). 10-((1-benzylpiperidin-2-yl) methyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione as a yellow-orange powder, 22% ( 127 mg) in yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.41 (br s, 3H), 1.57 (m, 2H), 1.77 (br s, 1H), 2.39 (s, 3H), 2.41 (s, 3H), 2.46 (s, 1H), 3.10 (m, 2H), 3.64 (d, 1H), 3.91 (d, 1H), 4.70 (br s, 1H), 4.95 (br s, 1H), 7.05 (s, 2H) , 7.11 (s, 3H), 7.62 (s, 1H), 7.88 (s, 1H), 11.27 (s, 1H). LC-MS mlz 430.0 [M + H] ⁺ , retention time 2.67 minutes.

Example 35

10-((1-benzylpyrrolidin-2-yl) methyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

<Reaction Scheme 7>

Step 1: Preparation of tert-butyl 2-(((2-amino-4,5-dimethylphenyl) amino) methyl) pyrrolidine-1-carboxylate

tert-butyl 2-(((2-amino-4,5-dimethylphenyl) amino) methyl) pyrrolidine-1-carboxylate is tert-butyl 2- (bromomethyl) pyrrolidine-1-car A neat mixture of carboxylate (475 mg, 1.8 mmol) and 4,5-dimethylbenzene-1,2-diamine (272 mg, 2.0 mmol) was produced and the resulting paste was synthesized by heating to 90 ° C. for 1.5 h. . The resulting liquid was cooled to room temperature and used without further purification in the next step. LC-MS mlz 319.9 [M + H], retention time 3.57 minutes.

Step 2: tert-Butyl 2-((7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) methyl) pyrrolidine- Preparation of 1-carboxylate

The resulting crude tert-butyl 2-(((2-amino-4,5-dimethylphenyl) amino) methyl) pyrrolidine-1-carboxylate (2.0 mmol) in AcOH (20 mL) at room temperature It was dissolved with oxalone monohydrate (336 mg, 2.1 mmol) and boric acid (247 mg, 4.0 mmol) and the resulting mixture was stirred at rt for 2.5 h. The reaction mixture was evaporated to dryness and added dry to silica gel (10 g) with MeOH. Column chromatography (0-20% MeOH in DCM) was performed and the product was separated as an impure mixture. This mixture was added to a preparative TLC plate using 10% MeOH in DCM and the plate was run using 5% MeOH in DCM as the mobile phase. The product was extracted from silica with MeOH and evaporated to tert-butyl 2-((7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridine-10 (2H ) -Yl) methyl) pyrrolidine-1-carboxylate (65 mg, 38% yield over 2 steps) was obtained as an oily film. LC-MS mlz 425.9 [M + H], retention time 6.40 minutes.

Step 3: 7,8-dimethyl-10- (pyrrolidin-2-ylmethyl) benzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetic acid salt

Tert-butyl 2-((7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) methyl) dyl in DCM (8 mL) To a solution of lollidine-1-carboxylate (65 mg, 0.15 mmol) was added TFA (2 mL) at room temperature. The resulting solution was stirred at room temperature for 4 hours and then the mixture was evaporated to 7,8-dimethyl-10- (pyrrolidin-2-ylmethyl) benzo [g] pteridine-2,4 (3H, 10H 66 mg (0.15 mmol, quantitative) of) -dione were obtained as an oily film. LC-MS mlz 325.9 [M + H], retention time 3.83 minutes.

Step 4: Preparation of 10-((1-benzylpyrrolidin-2-yl) methyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

The TFA salt of 7,8-dimethyl-10- (pyrrolidin-2-ylmethyl) benzo [g] pteridin-2,4 (3H, 10H) -dione (25 mg, 0.077 mmol) was dissolved in MeOH and Et. Dissolve in a 1: 1 mixture of ₃ N (15 mL), dry under reduced pressure, and dissolve in MeOH (5 mL) at room temperature. Benzaldehyde (10 mg, 0.094 mmol) and AcOH (1 drop) are added, the solution is stirred at room temperature for 3.5 hours, then NaBH ₃ CN (10 mg, 0.15 mmol) is added in one portion and the resulting solution is added at room temperature. Stir for 16 hours. The reaction was terminated with H ₂ O (3 drops) and the reaction mixture was evaporated. The crude product was purified by preparative TLC (10% MeOH in DCM) to give 10-((1-benzylpyrrolidin-2-yl) methyl) -7,8-dimethylbenzo [g] pteridine-2, 4 (3H, 10H) -Dione (4.5 mg, 14%) was obtained as a yellow powder.

¹ H NMR (400 MHz, MeOD) δ 1.58 (m, 1H), 1.73 (m, 1H), 2.08 (m, 5H), 2.48 (s, 3H), 2.56 (s, 3H), 3.43 (s, 2H ), 4.51 (m, 2H), 6.68 (d, 2H), 6.89-6.97 (m, 3H), 7.71 (s, 1H), 7.88 (s, 1H). LC-MS mlz 416.1 [M + H], retention time 2.35 minutes.

Example 36

7,8-dimethyl-10- (3- (tetrahydro-2H-pyran-4-yl) propyl) benzo [g] pteridine-2,4 (3H, 10H) -dione

Step 1: Preparation of 4,5-dimethyl-2-nitro-N- (3- (tetrahydro-2H-pyran-4-yl) propyl) aniline

4,5-dimethyl-2-nitro-N- (3- (tetrahydro-2H-pyran-4-yl) propyl) aniline is 1-bromo-4,5-dimethyl-2- in DMSO (1 mL) A solution of nitrobenzene (115 mg, 0.5 mmol) and 3- (tetrahydro-2H-pyran-4-yl) propan-1-amine (commercially available) (143 mg, 1.0 mmol) was heated at 130 ° C. for 35 minutes. And then heated at 160 ° C. for 10 minutes. The resulting mixture was diluted in EtOAc (25 mL) and H ₂ O (75 mL) and basified to pH 9 with 1N NaOH. The organic phase was then washed with H ₂ O (100 mL), dried over Na ₂ SO ₄ , filtered and evaporated. The resulting solid was added to silica gel in dry state and purified by column chromatography (EtOAc / hexanes, gradient 0-100% EtOAc) to afford 18 mg (12% yield) of the desired product as an orange solid. LC-MS mlz 293.0 [M + H], retention time 5.55 minutes.

Step 2: 4,5-dimethyl-N ^One Preparation of-(3- (tetrahydro-2H-pyran-4-yl) propyl) benzene-1,2-diamine

4,5-dimethyl-N ^1- (3- (tetrahydro-2H-pyran-4-yl) propyl) benzene-1,2-diamine is 4,5-dimethyl-2-nitro-N- (3-tetra Hydro-2H-pyran-4-yl) propyl) aniline (18 mg, 0.062 mmol) in Pd / C (10% Pd / C, 3% Pd) in MeOH (5 mL) and EtOAc (5 mL) at room temperature under Ar. w / w) and catalytic reduction with NaBH ₄ (5 mg, 0.13 mmol). After 30 minutes, the reaction mixture was filtered through Celite with EtOAc (15 mL) followed by MeOH (15 mL) to elute the product. The solvent is then evaporated to afford 4,5-dimethyl-N ^1- (3- (tetrahydro-2H-pyran-4-yl) propyl) benzene-1,2-diamine (quantitative) as a mixture of borate salts Used in the next step without further purification.

Step 3: Preparation of 7,8-dimethyl-10- (3- (tetrahydro-2H-pyran-4-yl) propyl) benzo [g] pteridine-2,4 (3H, 10H) -dione

7,8-dimethyl-10- (3- (tetrahydro-2H-pyran-4-yl) propyl) benzo [g] pteridin-2,4 (3H, 10H) -dione is crude 4,5- Dimethyl-N ^1- (3- (tetrahydro-2H-pyran-4-yl) propyl) benzene-1,2-diamine (0.062 mmol), oxalone monohydrate (11 mg, 0.069 mmol) and boric acid (8 mg , 0.13 mmol) was produced by stirring in AcOH (5 mL) at room temperature for 16 hours. The reaction mixture was evaporated to dryness, dissolved in DCM (25 mL) and H ₂ O (50 mL), the organic phase washed with brine (2 × 40 mL), dried over Na ₂ SO ₄ , filtered and , Evaporation to afford a solid, which was purified by preparative TLC (5% MeOH / DCM followed by 10% MeOH / DCM) to afford the desired product (11 mg, 48%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.15 (m, 2H), 1.24 (s, 1H), 1.42 (t, 2H), 1.60 (d, 2H), 1.74 (t, 2H), 2.41 (s, 3H), 3.28 (t, 2H), 3.84 (t, 2H), 4.57 (t, 2H), 7.81 (s, 1H), 7.92 (s, 1H), 11.31 (s, 1H). LC-MS mlz 369.2 [M + H], retention time 3.25 minutes.

Example 37

10- (3-cyclohexylpropyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

Step 1: Preparation of N- (3-cyclohexylpropyl) -4,5-dimethylbenzene-1,2-diamine

(3-bromopropyl) cyclohexane (1.20 g, 5.8 mmol), 4,5-dimethyl-o-phenylenediamine (3.18 g, 23.4 mmol) in toluene (30 mL), sodium bicarbonate (0.98 g, 11.7 mmol) ) And tetra-n-butylammonium iodide (0.22 g, 0.58 mmol) were stirred at 70 ° C. under nitrogen for 18 hours. The reaction was cooled to room temperature, partitioned between water and ethyl acetate (100 mL each), the layers separated and the aqueous layer extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was treated by silica gel chromatography (230-400 mesh, 150 g, eluted with 20% ethyl acetate / hexanes) to yield 1.0 g (66%) of the desired product as an oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90 (2 H, m), 1.24 (6 H, m), 1.67 (7 H, m), 2.13 (3 H, s), 2.18 (3 H, s) , 3.05 (2 H, t), 3.18 (3 H, br s), 6.46 (1 H, s), 6.53 (1 H, s); MS (ESI ⁺ ) m / z 261.2 (M + H) ⁺ for C ₁₇ H ₂₈ N ₂ , HPLC retention time: 3.93 min. (System D).

Step 2: Preparation of 10- (3-cyclohexylpropyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

A mixture of N- (3-cyclohexylpropyl) -4,5-dimethylbenzene-1,2-diamine (0.165 g, 0.63 mmol), alloxane (101 mg, 0.63 mmol) and boric acid (118 mg, 1.9 mmol) To acetic acid (5 mL) was added. The reaction was then stirred at rt for 18 h. Acetic acid was removed under vacuum. The residue was suspended in water, the precipitate collected, washed with water and air dried. The solid was treated by silica gel chromatography (Silicycle, 230-400 mesh, 50 g, eluted with 2% MeOH / DCM) to give 134 mg (58%) of the product as an amorphous yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.88 (2 H, m), 1.26 (6 H, m), 1.67 (7 H, m), 2.40 (3 H, s), 4.54 (2 H, m), 7.77 (1 H, s), 7.90 (1 H, s), 11.29 (1 H, s); MS (ESI ⁺ ) for C ₂₁ H ₂₆ N ₄ O ₂ m / z 367.3 (M + H) ⁺ , HPLC retention time: 4.20 min. (System D).

Example 38

7,8-dimethyl-10- (3-pyridin-3-ylpropyl) benzo [g] pteridine-2,4 (3H, 10H) -dione

Step 1: Preparation of 4,5-dimethyl-2-nitro-N- (3-pyridin-3-ylpropyl) aniline

4,5-dimethyl-2-nitroaniline (0.55 g) in 20 ml of DMF cooled with 60% sodium hydride (60:40, sodium hydride: mineral oil, 0.146 g, 3.64 mmol) in mineral oil under N ₂ in an ice bath. , 3.3 mmol) in solution. When gas evolution ceased, the ice bath was removed and the mixture was stirred for 30 minutes at room temperature. 3- (3-bromopropyl) pyridine [ Helv. Chim. Acta , 1982, 65 (6), 1864] (0.795 g, 3.97 mmol) was added and the mixture was stirred at rt overnight. DMF was evaporated and the residue was distributed between 30 ml EtOAc and 30 ml saturated aqueous NH ₄ Cl. The layers were separated and the aqueous phase extracted with 3 × 20 mL of EtOAc. The organic layer was dried over Na ₂ SO ₄ and evaporated to yield 1.0 g of a dark red solid. Silica gel chromatography (50 g, eluted with 5% EtOAc / CH ₂ Cl ₂ ) gave 0.25 g (26%) of the desired product as a red solid. MS (ESI ⁺ ) m / z 286 (M + H) ⁺ for C ₁₆ H ₁₉ N ₃ O ₂ .

Step 2: Preparation of 4,5-dimethyl-N- (3-pyridin-3-ylpropyl) benzene-1,2-diamine

4,5-dimethyl-2-nitro-N- (3-pyridin-3-ylpropyl) aniline (0.255 g, 0.894 mmol) was added to nickel (0.0262 g, 0.447 mmol) as a solution in EtOH (10 mL) and The mixture was stirred at rt under H ₂ . After 1 h, nickel was removed by filtration through Celite 545 and the filtrate was evaporated to afford the desired product (0.22 g, 96%) as an oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, 1 H), 8.48 (dd, 1 H), 7.55 (d, 1 H), 7.24 (dd, 1 H), 6.56 (s, 1 H) , 6.44 (s, 1H), 3.21 (m, 3H), 3.15 (t, 2H), 2.79 (t, 2H), 2.18 (s, 3H), 2.15 (s, 3H), 2.02 (d , 2 H).

Step 3: Preparation of 7,8-dimethyl-10- (3-pyridin-3-ylpropyl) benzo [g] pteridine-2,4 (3H, 10H) -dione

4,5-dimethyl-N- (3-pyridin-3-ylpropyl) benzene-1,2-diamine (0.220 g, 0.862 mmol), alloxane (0.14 g, 0.86 mmol) and diboron trioxide (0.18 g, 2.6 5 ml of HOAc was added to the mixture). The mixture was then shaken at 60 ° C. for 1 hour. Acetic acid was removed in vacuo and the remaining solid was taken up in 20 mL of H ₂ O. Saturated aqueous NaHCO ₃ was added to adjust the pH of the mixture to about 7 and the mixture was extracted with 3 × 20 mL of CH ₂ Cl ₂ . The organics were combined, dried over anhydrous sodium sulfate and concentrated. Silica gel chromatography (15 g, eluted with 3% MeOH / CH ₂ Cl ₂ ) afforded the desired product (10 mg) as a yellow solid. HPLC retention time: 2.28 min (System D).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.32 (s, 1 H), 8.49 (d, 1 H), 8.41 (d, 1 H), 7.91 (s, 1 H), 7.66 (m, 2H ), 7.32 (dd, 1H), 4.63 (t, 2H), 2.82 (d, 2H), 2.50 (m, 6H), 2.40 (m, 2H).

Example 39

8- (dimethylamino) -7-methyl-10- [3- (1H-pyrrol-1-yl) propyl] benzo [g] pteridin-2,4 (3H, 10H) -dione

8-Chloro-7-methyl-10- [3- (1H-pyrrole-1-yl) propyl] benzo [g] pteridine-2,4 (3H, 10H in N-methylpyrrolidinone (2.50 mL) To a solution of) -dione (120 mg, 0.32 mmol) was added a solution of dimethylamine (2.0 M, 0.985 mL, 1.97 mmol) in tetrahydrofuran. The test tube was sealed and the mixture was stirred at 80 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography (230-400 mesh, CH ₂ Cl ₂ /0.07 N methanolic ammonia (0.5-1.5%) as eluent) to 55 mg (45%). ) The desired product was obtained as an amorphous red solid.

¹ H NMR (DMSO-d ₆ ) δ 2.18 (p, 2 H), 2.42 (s, 3 H), 2.98 (s, 3 H), 3.33 (s, 3 H), 4.11 (t, 2 H), 4.47 (br t, 2H), 6.01 (d, 2H), 6.52 (s, 1H), 6.89 (d, 2H), 7.78 (s, 1H), 11.13 (s, 1H); MS (ESI ⁺ ) m / z 379.1 (M + H) ⁺ for C ₂₀ H ₂₂ N ₆ O ₂ , HPLC retention time: 3.31 min. (Method G).

Example 40

7,8-dimethyl-10- (3-pyridin-2-ylpropyl) benzo [g] pteridine-2,4 (3H, 10H) -dione

Step 1: Preparation of 4,5-dimethyl-2-nitro-N- (3-pyridin-2-ylpropyl) aniline

1-bromo-4,5-dimethyl-2-nitrobenzene (1.04 g, 4.54 mmol in toluene (16 mL); prepared as described in Chemistry-A European Journal , 2005, 11, 6254), 3-pyridin-2-ylpropan-1-amine (412 mg, 3.02 mmol; prepared as described in J. Med. Chem , 1969, 10 (3), 498-499), cesium carbonate (1.97 g, 6.05 mmol) and a well stirred slurry of oxydi-2,1-phenylene) bis [diphenylphosphine (244 mg, 0.454 mmol) was washed with nitrogen (four times) and tris (dibenzylideneacetone Dipalladium (0) (138 mg, 0.151 mmol) was added and the mixture was heated to 80 ° C. overnight. The reaction was cooled to room temperature and filtered (4 × 5 mL toluene rinse). The filtrate was shaken with 0.2N HCl (6 × 30 mL) and the combined aqueous layers (red) were made basic (pH 10-11) with aqueous K ₂ CO ₃ and extracted with DCM (6 × 40 mL). The combined DCM layers were stripped anhydrous to give 755 mg (83%) of the desired product as a red solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50-8.63 (1 H, m), 8.06 (1 H, br s), 7.92 (1 H, s), 7.56-7.65 (1 H, m), 7.10- 7.22 (2 H, m), 6.61 (1 H, s), 3.31-3.42 (2 H, m), 2.95 (2 H, t), 2.25 (3 H, s), 2.19-2.24 (2 H, m ), 2.17 (3H, s); MS (ESI ⁺ ) m / z 286.19 (M + H) ⁺ for C ₁₆ H ₁₉ N ₃ O ₂ .

Step 2: Preparation of 4,5-dimethyl-N- (3-pyridin-2-ylpropyl) benzene-1,2-diamine

A stirring mixture of 4,5-dimethyl-2-nitro-N- (3-pyridin-2-ylpropyl) aniline, EtOH (30 mL) and Raney nickel (1 mL slurry, 200 mmol) was flushed with N ₂ After treatment, the mixture was stirred under H ₂ (1 atmosphere). After stirring overnight, the mixture was filtered through celite (5 × 5 mL MeOH rinse), stripped to a brown solid (0.63 g, 99%) and used in the next step without further purification. MS (ESI ⁺ ) m / z 256.23 (M + H) ⁺ for C ₁₆ H ₂₁ N ₃ .

Step 3: Preparation of 7,8-dimethyl-10- (3-pyridin-2-ylpropyl) benzo [g] pteridine-2,4 (3H, 10H) -dione

4,5-dimethyl-N- (3-pyridin-2-ylpropyl) benzene-1,2-diamine (0.63 g, 2.5 mmol), siloxane monohydrate (0.434 g, 2.71 mmol), boric acid (0.458 g, 7.40 mmol) and an N ₂ -flushed mixture of acetic acid (40 mL) were stirred at room temperature. After stirring overnight, the reaction mixture was filtered through a sintered glass funnel and the remaining solids were AcOH (4 × 1 mL), DCM (5 × 1 mL), EtOAc (5 × 1 mL), water (5 × 1 mL). ) And finally with acetone (5 × 1 mL). The remaining solid was dried under high vacuum to afford the desired product as a yellow solid (0.37 g, 41%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.31 (1H, s), 8.49-8.54 (1 H, m), 7.91 (1 H, br s), 7.77 (1 H, br s) 7.68-7.74 (1 H, m), 7.29-7.36 (1 H, m), 7.20-7.27 (1 H, m), 4.59-4.79 (2 H, m), 2.90-3.06 (2 H, m), 2.49 (3 H, s), 2.42 (3H, s), 2.07-2.26 (2H, m); MS (ESI ⁺ ) for C ₂₀ H ₁₉ N ₅ O ₂ m / z 362.09 (M + H) ⁺ . HPLC retention time: 2.32 min. (System E).

Other compounds of the invention were prepared and characterized using the methods described above and by selecting the appropriate starting materials. These compounds are summarized in Table 2 below with the examples described above.

Synthesis of Compounds of Formulas I (B) to V (B) of the Invention

The synthesis of the compounds of formulas I (B) to V (B) of the present invention is shown below. Temperature is given in degrees Celsius (° C.); Operation is carried out at room temperature or room temperature unless otherwise indicated, ie at temperatures in the range 18 ° C. to 25 ° C. Chromatography means flash chromatography on silica gel; Thin layer chromatography (TLC) was performed on silica gel plates. Samples were dissolved in deuterated solvents for NMR spectroscopy. NMR data are expressed as delta values of major diagnostic protons, presented in parts per million (ppm) for the appropriate solvent signal. Conventional abbreviations for signal forms were used. For mass spectra (MS), the lowest mass major ions were recorded for the molecules where isotope splitting produced multiple mass spectral peaks. The solvent mixture composition is presented in volume percentages or volume ratios. If the NMR spectra were complex, only the diagnostic signal was recorded.

<Scheme 1>

<Reaction Scheme 2>

<Reaction Scheme 3>

<Reaction Scheme 4>

Scheme 5

<Reaction Scheme 6>

<Reaction Scheme 7>

<Reaction Scheme 8>

General Methods for Analytical HPLC Analysis :

Method A ′ : Analytical HPLC was performed using Luna Prep C ₁₈ , 100 × 5 μm, 4.6 × 100 mm columns. The aqueous phase was 0.1% TFA in USP water. The organic phase was 0.1% TFA in acetonitrile. Elution profiles are as follows: 95% aqueous (0 to 0.5 minutes); Organic gradient from 95% aqueous to 98% (0.5 to 10.5 min); 98% organic (2 minutes); Gradient from 98% organic to 95% aqueous (5.5 min); 95% aqueous (1 min).

Method C ′ : Analytical LCMS was performed using a YMC Combiscreen ODS-AQ, 5 μm, 4.6 × 50 mm column. The aqueous phase was 1% 2 mM NH ₄ OAc in 90:10 IPA: H ₂ O, 0.03% TFA in USP water. The organic phase was 1% 2 mM NH ₄ OAc in 90:10 IPA: H ₂ O, 0.03% TFA in acetonitrile. The elution profile is as follows: gradient from 95% aqueous to 100% organic (0-6 min); 100% organic (1 min); 95% aqueous gradient at 100% organic (0.1 min); 95% aqueous (2.9 min).

Method D ' : Agilent 1100 HPLC, Agilent XDB C ₁₈ 50 × 4.6 mm 1.8 micron column, 1.5 mL / min, solvent A-water (0.1% TFA), solvent B-acetonitrile (0.07% TFA), gradient-5 min 95% B from 95% A; Hold for 1 minute; Then recycle, UV detection at about 210 and 254 nm.

System G ' : Agilent 1100 HPLC, Agilent XDB C ₁₈ 50 × 4.6 mm 5 micron column, 1.5 mL / min, solvent A-water (0.1% TFA), solvent B-acetonitrile (0.07% TFA), gradient-6 min 95% B from 95% A; Hold for 1 minute; Then recycle, UV detection at about 210 and 250 nm.

Method F ′ : Analytical HPLC was performed using Luna Prep C ₁₈ , 100 × 5 μm, 4.6 × 100 mm columns. The aqueous phase was 0.1% TFA in USP water. The organic phase was 0.1% TFA in acetonitrile. Elution profiles are as follows: gradient from 95% aqueous to 60% aqueous (0-10 min); Second gradient from 60% aqueous to 2% aqueous (2 minutes); 2% aqueous (1 min); 95% aqueous (4 min) from 2% aqueous.

General Procedure for Preparative HPLC Conditions

Method 1 ′ : Preparative HPLC was performed using a SunFire ™ Prep C ₁₈ OBD ™ 5 μm, 30 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was acetonitrile. Elution profiles are as follows: 100% aqueous (0-3 min); Gradient from 100% aqueous to 98% organic (3 to 21 min); 98% organic (1 min); Gradient from 98% organic to 95% aqueous (1 min); 95% aqueous (1 min).

Method 2 ′ : Preparative HPLC was performed using a SunFire ™ Prep C ₁₈ OBD ™ 5 μm, 30 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was acetonitrile. Elution profiles are as follows: gradient from 95% aqueous to 25% organic (0-10 min); Second gradient from 25% organic to 98% organic (at least 2.5 minutes); Third gradient to 95% aqueous (at least 1 minute).

Method 4 ′ : SunFire ™ Prep C ₁₈ OBD ™ 5 μm, 30 × 100 mm column. The aqueous phase was 0.1% TFA in USP water. The organic phase was acetonitrile. Elution profiles are as follows: gradient from 100% aqueous to 60% organic (0 to 29 minutes); Then 98% organic (29-31 min); 98% organic (2 minutes); Gradient from 98% organic to 100% aqueous (2 minutes); 100% aqueous (2 minutes).

Terms and abbreviations :

ACN = acetonitrile,

AcOH = acetic acid,

Bn = benzyl,

t-BuOH = tert-butyl alcohol,

Cat. = Catalytic amount,

CAN = cerium ammonium nitrate (IV),

CBzCl = benzyl chloroformate,

Conc. = Dark,

D-ribose = (2R, 3R, 4R) -2,3,4,5-tetrahydroxypentane,

DIAD = diisopropyl azodicarboxylate,

DIPEA = diisopropylethylamine,

DMF = N, N-dimethylformamide,

DCM = dichloromethane,

DMAP = N, N-dimethylaminopyridine,

DMSO = dimethyl sulfoxide,

Et ₂ O = diethyl ether,

Et ₃ N = triethyl amine,

EtOAc = ethyl acetate,

EtOH = ethyl alcohol,

equiv. = Equivalent (s),

h = time (s),

H ₂ O = water,

HATU = 2- (1H-7-abenzobenzotriazol-1-yl) -1,1,3,3-tetramethyl uronium hexafluorophosphate methanealuminum,

HBTU = 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate,

HCl = hydrochloric acid,

HPLC = high performance liquid chromatography,

HOAc = acetic acid,

IPA = isopropyl alcohol,

ISCO = normal phase silica gel cartridge supplied by Teledyne ISCO,

K ₂ CO ₃ = potassium carbonate,

Min. = Minute (s),

MgCl ₂ = magnesium chloride,

MeOH = methanol

MW = microwave,

NaHCO ₃ = sodium bicarbonate,

Na ₂ SO ₄ = sodium sulfate,

NH ₄ OH = ammonium hydroxide,

NH ₄ OAc = ammonium acetate,

NMR = nuclear magnetic resonance,

PMB = p-methoxybenzyl,

POCl ₃ = phosphorus oxychloride,

POMCl = pivaloyloxymethyl chloride,

PPh ₃ = triphenylphosphine,

Prep = Preparative,

PyBOP = benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,

rt = room temperature,

RNA = ribonucleic acid,

Endoribonuclease that specifically degrades single-stranded RNA at the RNase T1 = G residue,

SOCl ₂ = thionyl chloride,

TBAI = tetrabutylammonium iodide,

TFA = trifluoroacetic acid,

TFAA = trifluoroacetic anhydride,

THF = tetrahydrofuran,

TLC = thin layer chromatography,

TMSBr = trimethylsilyl bromide,

Tris HCl = tris (hydroxymethyl) aminomethane hydrochloride,

USP water = US Pharmacopoeia (USP) grade water.

Intermediate 1 (B)

Preparation of 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde

To a suspension of riboflavin (8.5 g, 0.0023 mol) in 2 N aqueous sulfuric acid (225 ml) cooled to 0 ° C. in a flask wrapped with tinfoil, add orthoguadioic acid (18.9 g, 0.0825 mmol) and add to water (200 ml) Dissolved. After 30 minutes, the reaction was allowed to warm to room temperature. Once the reaction mixture became clear (clear yellow solution), the sodium carbonate was added to carefully adjust the pH of the reaction solution to 3.8-3.9 (using a pH meter). (It is very important to carefully control the pH, otherwise the product will not precipitate out of solution). The precipitate was separated by filtration and washed freely with cold water, ethanol and diethyl ether to afford the desired product (6.04 g, 94%) as an orange solid. LC-MS mlz 285.1 [M + H] ⁺ , retention time 1.63 minutes.

General procedure 1

2- (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -acetaldehyde (1 mmol) in MeOH (43 mL) To the suspension of is added an appropriately substituted amine (3 mmol) and AcOH (0.28 mL), respectively, and stirred at room temperature for 2 hours, wherein the substituted amine, for example (1) HN (R) (R ') HN (R ₄ ) -A, wherein R ₄ and A are as defined in Formula I (B); Or (2) HN (R) (R ′) may represent HN (R ₄ ) (R ₅ ), wherein R ₄ and R ₅ are as defined in Formula III (B); Or (3) HN (R) (R ') together with acetaldehyde forms Y, wherein Y is as defined in Formula II (B), provided that Y in this example is -CH ₂ C (O) N Except for (H) -C ₄ H ₅ -Cl or -CH ₂ CH ₂ CH ₂ N (H) benzyl. NaCNBH ₃ (3 mmol) was added to the reaction mixture and stirred at room temperature for 24 hours to allow -CH ₂ CH ₂ N (R) (R ') to be -Alk- (X) as defined in Formula (B). -A; (2) —CH ₂ CH ₂ N (R ₄ ) (R ₅ ) as defined in Formula III (B); Or (3) Y as defined in formula II (B) but in this case Y is -CH ₂ C (O) N (H) -C ₄ H ₅ -Cl or -CH ₂ CH ₂ CH ₂ N (H If Y is —CH ₂ C (O) N (H) —C ₄ H ₅ —Cl or —CH ₂ CH ₂ CH ₂ N (H) benzyl, except when not benzyl, the compounds may be Can be produced using various procedures]. A product as shown in the above formula is obtained. The solvent was removed in vacuo and the crude product was purified by preparative HPLC. The combined fractions were lyophilized to give the desired product [NMR, LC-MS].

General procedure 2

Suspension of (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) -acetaldehyde (1 mmol) in methanol (28 mL) To the appropriately substituted amine (1 mmol) at room temperature, for example here substituted amines, for example (1) HN (R) (R ') represents HN (R ₄ ) -A and R ₄ And A is as defined in formula (I); Or (2) HN (R) (R ') may represent HN (R ₄ ) (R ₅ ), wherein R ₄ and R ₅ are as defined in Formula III (B); Or (3) HN (R) (R ') together with acetaldehyde forms Y, wherein Y is as defined in Formula II (B), but in this example Y is -CH ₂ C (O) N ( Except for H) -C ₄ H ₅ -Cl or -CH ₂ CH ₂ CH ₂ N (H) benzyl. After 30 minutes acetic acid (0.57 mL) and sodium cyanoborohydride (4.375 mmol) are added and the solution is stirred for 6 hours to give the product as shown in the above formula, wherein -CH ₂ CH ₂ N (R) (R ') is -Alk- (X) -A as defined in formula (I); (2) —CH ₂ CH ₂ N (R ₄ ) (R ₅ ) as defined in Formula III (B); Or (3) Y as defined in formula II (B), in which case Y is —CH ₂ C (O) N (H) —C ₄ H ₅ —Cl or —CH ₂ CH ₂ CH ₂ N ( H) except non-benzyl [If Y is —CH ₂ C (O) N (H) —C ₄ H ₅ —Cl or —CH ₂ CH ₂ CH ₂ N (H) benzyl, the compound is described herein. Can be produced using various procedures]. A product as shown in the above formula is obtained. The reaction mixture was concentrated and the residue was added to dryness on silica and purified by column chromatography (gradient 3-10% MeOH) using MeOH in DCM as eluent. The desired product [NMR, LC-MS] was isolated after evaporation of the appropriate fractions.

Example 41

N- (4-((2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) amino) phenyl) Acetamide

The title compound uses the general procedure 2, and (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] ptridin-10-yl) -acetaldehyde (50 Mg, 0.176 mmol) and N- (4-aminophenyl) acetamide (26.4 mg, 0.176 mmol). The desired product was obtained as a dark brown powder (37.7 mg, 51%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.97 (s, 3H), 2.31 (s, 3H), 2.37 (s, 3H), 3.50 (m, 2H), 4.70 (m, 2H), 5.54 ( t, 1H), 6.59 (d, 2H), 7.31 (t, 2H), 7.53 (s, 1H), 7.88 (s, 1H), 9.55 (s, 1H), 11.33 (s, 1H). MS m / z 419.2 [M + H] ⁺ , 441.3 [M + Na] ⁺ .

Example 42

10- (2-((2- (dimethylamino) ethyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

The title compound uses the general procedure 2, and (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] ptridin-10-yl) -acetaldehyde (50 Mg, 0.176 mmol) and N ¹ , N ¹ -dimethylethane-1,2-diamine (16 mg, 0.176 mmol). The reaction mixture was concentrated and the residue was added to silica gel in dry state and purified by column chromatography using MeOH (20%) in DCM using as eluent with 1% Et ₃ N. 10- (2-((2- (dimethylamino) ethyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (46.5 mg, 74%) Was separated after evaporation of the appropriate fractions.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.11 (s, 6H), 2.26 (t, 2H), 2.39 (s, 3H), 2.43 (s, 3H), 2.64 (t, 2H), 2.91 ( t, 2H), 3.36 (br s, H ₂ O), 4.65 (t, 2H), 7.87 (s, 1H), 7.88 (s, 1H). MS m / z 357.3 [M + H] ⁺ .

Example 43

10- (2-(((2-hydroxypyridin-4-yl) methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

Step 1: Preparation of 10- (2- (benzylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetate

Step 2: Preparation of 10- (2- (benzylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

The title compound is 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pterridin-10 (2H) -yl) acetaldehyde (2.08 g, 7.32 mmol) and Benzylamine (4 mL, 34.3 mmol) in 1 mmol 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] ptridin-10-yl)- Produced using general procedure 1, except that acetaldehyde and amine (3 mmol) were used instead of each. The product was contaminated with 10- (2- (benzyl (methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione. The next two steps were carried out to separate the desired product.

Step 3: tert-Butyl benzyl (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) carbamate Manufacture

To a solution of crude 10- (2- (benzylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (7.53 mmol) in MeOH (200 mL) Di-tert-butyl dicarbonate (5.2 g, 23.8 mmol) and Et ₃ N (4 mL) were added. The reaction was concentrated under reduced pressure and purified by silica gel chromatography (ISCO) (10% MeOH / DCM from 100% DCM) to afford the desired product (1.85 g, 54%) as a brown solid.

Step 4: Preparation of 10- (2- (benzylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetate

Tert-butyl benzyl (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) in DCM (2 mL) To a solution of carbamate (50 mg, 0.11 mmol) was added TFA (2 mL) at room temperature. After 2 hours, the reaction mixture was concentrated and the remaining material was dissolved in MeOH (10 mL) and purified by preparative HPLC (Method 2 ′). The combined fractions were lyophilized (LCMS) to afford the desired product (33.6 mg, 65%) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.42 (s, 3H), 2.53 (s, 3H), 4.35 (s, 2H), 5.00 (m, 2H), 7.43 (m, 3H), 7.52 ( m, 2H), 7.83 (s, 1H), 7.96 (s, 1H), 9.02 (s, 2H), 11.49 (s, 1H).

Step 5: Preparation of 10- (2-aminoethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione-2,2,2-trifluoroacetate salt

10- (2- (benzylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (step 4) in anhydrous EtOH (100 mL) (395 mg, 1.05 mmol) and Pd / C (75 mg) were hydrogenated overnight at 30 psi and 45 ° C. The mixture was filtered through a pad of celite. The filtrate was concentrated to anhydrous under reduced pressure to give crude product (230 mg, 77%). The crude product (19.5 mg, 0.07 mmol) was dissolved in MeOH (8 mL) and purified by preparative HPLC (Method 2 ′). Lyophilization of the combined fractions gave the desired product (5.0 mg, 14%) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.42 (s, 3H), 2.50 (s, 3H), 4.20 (m, 2H), 4.87 (m, 2H), 7.81 (s, 1H), 7.88 ( m, 2H), 7.97 (s, 1 H), 11.45 (s, 1 H).

Step 6: 10- (2-((2-methoxypyridin-4-yl) methylamino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione Produce

2-into a suspension of 10- (2-aminoethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (46 mg, 0.16 mmol) in MeOH (5 mL). Methoxyisonicotinaldehyde (C. Subramanyam, M. Noguchi and SM Weinreb, J. Org. Chem ., 1989, 54, 5580), the contents of which are incorporated herein by reference in their entirety. (22 mg, 0.16 mmol) followed by acetic acid (0.1 mL) at room temperature. After 30 minutes, sodium cyanoborohydride (30 mg, 0.47 mmol) was added and the solution was stirred for 16 hours. The reaction mixture was concentrated and the residue was dissolved in DMF (4 mL) / water (3 mL), filtered and purified by preparative HPLC (Method 2 ′). Lyophilization of the combined fractions afforded the desired product (6.5 mg, 10%).

¹ H NMR (400 MHz, CD ₃ OD) δ 2.50 (s, 3H), 2.63 (s, 3H), 3.70 (m, 2H), 3.94 (s, 3H), 4.37 (s, 2H), 5.10 (m , 2H), 6.95 (s, 1H), 7.08 (d, 1H), 7.81 (s, 1H), 7.96 (s, 1H), 8.21 (d, 1H).

Step 7: 10- (2-(((2-hydroxypyridin-4-yl) methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H)- Preparation of Dion

10- (2-(((2-methoxypyridin-4-yl) methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione (9 Mg, 0.02 mmol) and NaI (43 mg, 0.26 mmol) were heated in acetic acid (5 mL) for 2 hours. Acetic acid was evaporated and water (10 mL) was added followed by sodium thiosulfate until the solution was clear. The solution was concentrated and the residue was dissolved in water (3 mL) and purified by preparative HPLC (Method 2 ′). Lyophilization of the combined fractions afforded the desired product (3.1 mg, 36%).

¹ H NMR (400 MHz, CD ₃ OD) δ 2.51 (s, 3H), 2.63 (s, 3H), 3.71 (m, 2H), 4.29 (s, 2H), 5.13 (m, 2H), 6.51 (d , 1H), 6.63 (s, 1H), 7.55 (d, 1H), 7.82 (s, 1H), 8.03 (s, 1H). ESI (+) [M + H] ⁺ = 393.1.

Example 44

N- (4-Chlorobenzyl) -2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetamide

Step 1: Preparation of (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -acetic acid

(7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo) in acetonitrile (2 mL), tert-butanol (8 mL) and methyl-1-cyclohexene (3 mL) [g] Sodium chlorite (122 g) in 2 ml of water at 0 ° C. in a suspension of pteridin-10-yl) -acetaldehyde (produced by the method of Example 1, step 1) (50 mg, 0.18 mmol) Mg, 1.35 mmol) and sodium dihydrogen phosphate (148 mg, 1.23 mmol) were added dropwise over 5 minutes. After 2 hours, the reaction mixture was diluted with water and the organic layer was removed. The aqueous phase was concentrated in vacuo and the resulting crude mixture was purified by preparative HPLC. (7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pterridin-10-yl) -acetic acid was isolated after lyophilization of the appropriate fraction (36 mg, 68%). LC-MS mlz 301.1 [M + H] ⁺ , Retention time = 1.68 min.

Step 2: N- (4-Chlorobenzyl) -2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acet Preparation of Amides

(7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo [g] pteridin-10-yl) acetic acid (100 mg, 0.34 mmol) in DMF (9 mL) and (4-chlorophenyl) methanamine (0.084 mL, 0.68 mmol) was stirred at 0 ° C. under argon for 10 minutes. DIPEA (0.18 mL, 0.68 mmol) was added to the reaction mixture, then HATU (128 mg, 0.68 mmol) was added and the mixture was stirred for 18 hours before allowing to warm to room temperature. Another 2 equivalents of DIPEA, (4-chlorophenyl) methanamine and HATU were added and the resulting mixture was stirred for another 48 hours at room temperature. The mixture was concentrated to 2 mL, diluted with Et ₂ O (5 mL) and the solids were removed by filtration. The filtrate was concentrated and MeOH was added to the residue. The precipitate was separated, washed with MeOH (5 mL), purified using preparative HPLC (Method 1 ′), and preparative TLC using 9/1 DCM / MeOH to give the desired product (3 mg). , 2%) was obtained as a yellow solid.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ 2.41 (s, 3H), 2.47 (s, 3H), 4.31 (s, 2H), 5.36 (s, 2H), 7.34 (m, 4H), 7.69 ( s, 1 H), 7.95 (s, 1 H), 8.78 (s, 1 H), 11.43 (s, 1 H).

Example 45

10- (2-(((1H-benzo [d] imidazol-5-yl) methyl) amino) ethyl-7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione Preparation of Trifluoroacetic Acid Salts

Step 1: Preparation of (1H-Benzo [d] imidazol-5-yl) methanamine

To a solution of 1H-benzo [d] imidazole-5-carbonitrile (0.212 g, 1.48 mmol) in 7N NH ₃ in MeOH (15 mL) was added Raney nickel slurry (0.0087 g, 0.148 mmol) in water. The reaction flask was placed under a hydrogen atmosphere (equipped with balloons) and stirred at room temperature for 18 hours. After 18 hours, an additional catalyst amount (0.0087 g, 0.000148 mol) of Raney nickel slurry in water was added to the reaction flask. The reaction was stirred under hydrogen atmosphere for an additional 18 hours. The reaction mixture was filtered through celite and concentrated. The crude reaction mixture was used for the next step. LC-MS mlz 148.0 [M + H] ⁺ , retention time 0.65 min.

Step 2: 10- (2-(((1H-Benzo [d] imidazol-5-yl) methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H)-Preparation of Dione

The title compound is prepared using general procedure 1, using 2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) acetaldehyde ( 0.05 g, 0.176 mmol) and 0.168 g (1.14 mmol, (1.14 mmol) of (1H-benzo [d] imidazol-5-yl) methanamine). The product is 10- (2-(((1H-benzo [d] imidazol-5-yl) methyl) (methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 ( Contaminated with 3H, 10H) -dione. Two steps were then performed to separate the product from the N-methyl by-product.

Step 3: tert-butyl ((1H-benzo [d] imidazol-5-yl) methyl) (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo [g] Preparation of Pteridin-10 (2H) -yl) ethyl) carbamate

Crude 10- (2-(((1H-benzo [d] imidazol-5-yl) methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2 in MeOH (200 mL) To a solution of, 4 (3H, 10H) -dione (0.176 mmol) was added di-tert-butyl dicarbonate (5.2 g, 23.8 mmol) and Et ₃ N (4 mL). The reaction was stirred for 4 hours, at which time the reaction mixture was concentrated. Purification was carried out using preparative TLC using 2% MeOH / DCM as solvent. The appropriate bands were collected, the silica gel was filtered off and the filtrate was concentrated. The product was isolated as a yellow solid (35.2 mg, 39%), which was used for the next step.

Step 4: 10- (2-(((1H-Benzo [d] imidazol-5-yl) methyl) amino) ethyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, Preparation of 10H) -Dione Trifluoro Acetic Acid

Tert-butyl ((1H-benzo [d] imidazol-5-yl) methyl) in DCM (2 mL) (2- (7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo To a solution of [g] pteridin-10 (2H) -yl) ethyl) carbamate (35.2 mg, 0.068 mmol) was added TFA (2 mL) at room temperature. After stirring for 4 hours, the reaction mixture was concentrated, the residual material was dissolved in DMSO (2 mL) and purified by preparative HPLC (Method 4 ′). Lyophilization of the combined pure fractions gave the desired product (27.3 mg, 37%) as a yellow solid. LC-MS mlz 416.1 [M + H] ⁺ , retention time 3.14 minutes.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.4 (s, 3H), 3.44 (m, 2H), 4.5 (m, 2H), 4.98 (m, 2H), 7.57 (m, 1H), 7.82 ( m, 2H), 7.94 (m, 2H), 9.12 (m, 3H), 11.43 (s, 1H). LC-MS mlz 416.1 [M + H] ⁺ , retention time 3.14 minutes.

Example 46

8- (cyclopentyloxy) -7-methyl-10- (2-((2- (trifluoromethyl) benzyl) amino) ethyl) benzo [g] pteridine-2,4 (3H, 10H)- Dione 2,2,2-trifluoroacetic acid salt

Step 1: Preparation of 2- (cyclopentyloxy) -1-methyl-4-nitrobenzene

A mixture of 2-methyl-5-nitrophenol (4.5 g, 29 mmol), bromocyclopentane (7.8 g, 52 mmol) and K ₂ CO ₃ was refluxed for 16 h in ACN (200 mL). The solid was removed by filtration and washed with EtOAc. The filtrate was concentrated and used in the next step.

Step 2: Preparation of 3- (cyclopentyloxy) -4-methylaniline

To a solution of 2- (cyclopentyloxy) -1-methyl-4-nitrobenzene (29 mmol) and Pd / C (200 mg, 10% wet) in MeOH (200 mL) was slowly added sodium borohydride (1.25) at 0 ° C. g, 33 mmol) was added with vigorous stirring. The resulting mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude product was dissolved in DCM and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the crude product (5.79 g) as a brown oil. This was used without further purification in the next step. LC-MS ESI (+) [M + H] ⁺ = 191.9, retention time 2.99 minutes.

Step 3: Preparation of tert-butyl (2-((3- (cyclopentyloxy) -4-methylphenyl) amino) ethyl) carbamate

A mixture of 3- (cyclopentyloxy) -4-methylaniline (2.36 g, 12.3 mmol) and tert-butyl (2-bromoethyl) carbamate (2.55 g, 11.3 mmol) was charged with DIPEA (4.2 mL, 24 mmol). Heated at 60 ° C. for 3 hours. The reaction was cooled to rt and EtOAc (20 mL) was added with stirring. The solid was removed by filtration and washed with EtOAc. The filtrate was evaporated and the residue was purified by flash column chromatography using gradient 0 to 40% EtOAc in hexane as eluent. The product was isolated as red oil (1.93 g, 50%). LCMS ESI (+) [M + H] ⁺ = 334.9, retention time 4.29 minutes.

Step 4: tert-butyl (2- (8- (cyclopentyloxy) -7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pterridin-10 (2H) -yl) Preparation of ethyl) carbamate

A mixture of tert-butyl (2-((3- (cyclopentyloxy) -4-methylphenyl) amino) ethyl) carbamate (2 g, 5.98 mmol) and bioleic acid (1.14 g, 6.5 mmol) was prepared at 145 ° C. Treatment with microwave for 90 min in EtOH (18 mL) and water (2 mL). The solvent was evaporated and the resulting solid was washed with Et ₂ O, EtOAc followed by water (2 mL). The product was isolated as a yellow solid (902 mg, 38%). The product was used without further purification in the next step. LCMS ESI (+) [M + H] ⁺ = 455.9, retention time 4.48 minutes.

Step 5: Preparation of 10- (2-aminoethyl) -8- (cyclopentyloxy) -7-methylbenzo [g] pteridine-2,4 (3H, 10H) -dione

Tert-butyl (2- (8- (cyclopentyloxy) -7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) in DCM (2 mL)) To a solution of -yl) ethyl) carbamate (57 mg, 0.12 mmol) was added TFA (2 mL) at room temperature. After stirring for 2 hours, the reaction mixture was concentrated, TEA (2 mL) was added to the residual material, stirred for 20 minutes, and concentrated to give crude oil. The crude (10- (2-aminoethyl) -8- (cyclopentyloxy) -7-methylbenzo [g] pteridine-2,4 (3H, 10H) -dione) was not further purified in the next step. Used without. LCMS: ESI (+) [M + H] ⁺ = 356.0

Step 6: 8- (cyclopentyloxy) -7-methyl-10- (2-((2- (trifluoromethyl) benzyl) amino) ethyl) benzo [g] pteridine-2,4 (3H, 10H)-Preparation of Dione

8- (cyclopentyloxy) -7-methyl-10- (2-((2- (trifluoromethyl) benzyl) amino) ethyl) benzo [g] pteridine-2,4 (3H, 10H)- Dione was prepared using the general procedure 1, and 10- (2-aminoethyl) -8- (cyclopentyloxy) -7-methylbenzo [g] pteridine-2,4 (3H, 10H) -dione (0.125 mmol). , Step 2) and 2- (trifluoromethyl) benzaldehyde (17.4 mg, 0.1 mmol). LCMS showed the product to be 8- (cyclopentyloxy) -7-methyl-10- (2- (methyl (2- (trifluoromethyl) benzyl) amino) ethyl) benzo [g] pteridine-2,4 It was found to be contaminated with (3H, 10H) -dione. Two steps were then performed to separate the product. LCMS: ESI (+) [M + H] ⁺ = 514.0, retention time 3.50 minutes (purpose product) and 528.0, retention time 3.61 minutes (N-methylated byproduct).

Step 7: tert-butyl (2- (8- (cyclopentyloxy) -7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pterridin-10 (2H) -yl) Preparation of ethyl) (2- (trifluoromethyl) benzyl) carbamate

Crude 8- (cyclopentyloxy) -7-methyl-10- (2-((2- (trifluoromethyl) benzyl) amino) ethyl) benzo [g] pteridine-2 in MeOH (200 mL) To a solution of, 4 (3H, 10H) -dione was added di-tert-butyl dicarbonate (54 mg, 0.25 mmol) and Et ₃ N (1 mL). The reaction mixture was stirred at rt for 5 h. The reaction was concentrated under reduced pressure and purified by preparative TLC using 3% MeOH / DCM as eluent. Pure tert-butyl (2- (8- (cyclopentyloxy) -7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridin-10 (2H) -yl) ethyl) (2- (trifluoromethyl) benzyl) carbamate (17.0 mg) was obtained as a light yellow solid.

Step 8: 8- (cyclopentyloxy) -7-methyl-10- (2-((2- (trifluoromethyl) benzyl) amino) ethyl) benzo [g] pteridine-2,4 (3H, Preparation of 10H) -Dione 2,2,2-trifluoroacetic Acid Salt

Tert-butyl (2- (8- (cyclopentyloxy) -7-methyl-2,4-dioxo-3,4-dihydrobenzo [g] pteridine-10 (2H) in DCM (1 mL)) To a solution of -yl) ethyl) (2- (trifluoromethyl) benzyl) carbamate (17 mg, 0.03 mmol) was added TFA (1 mL) at room temperature. After stirring for 2 hours, the reaction mixture is concentrated and lyophilized. 8- (cyclopentyloxy) -7-methyl-10- (2-((2- (trifluoromethyl) benzyl) amino) ethyl) benzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetic acid salt (12.4 mg, 71%) was obtained as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.67-1.83 (m, 6H), 2.02 (m, 2H), 2.28 (s, 3H), 3.57 (t, 2H), 4.50 (s, 2H), 5.10 (t, 2H), 5.30 (m, 1H), 7.14 (s, 1H), 7.70 (m, 1H), 7.78 (m, 2H), 7.84 (d, 1H), 7.98 (s, 1H), 9.49 (br s, 2 H), 11.41 (s, 1 H). ESI (+) [(M-TFA) + H] ⁺ = 514.1

Example 47

10- (3- (benzylamino) propyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetic acid salt

Step 1: N ^One Preparation of-(4,5-dimethyl-2-nitrophenyl) propane-1,3-diamine

N ^1- (4,5-dimethyl-2-nitrophenyl) propane-1,3-diamine is a mixture of 1-bromo-4,5-dimethyl-2-nitrobenzene (230 mg, 1.0 mmol) and propane-1, A knit mixture of 3-diamine (2 mL, excess) was produced by heating at 160 ° C. for 4 hours. The resulting mixture was evaporated to dryness, dissolved in DCM (40 mL) and extracted with 2 M HCl (2 × 30 mL). The aqueous phase was washed with DCM (2 × 30 mL) and then made basic to pH 13 with 2N NaOH (61 mL). The cloudy aqueous phase was extracted with DCM (3 × 30 mL) and CHCl ₃ (2 × 30 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to give N ^1- (4,5-dimethyl-2-nitrophenyl) propane-1,3-diamine (191 mg) as an orange solid. LC-MS mlz 224.0 [M + H], retention time 4.18 min.

Step 2: N ^One -Benzyl-N ³ Preparation of-(4,5-dimethyl-2-nitrophenyl) propane-1,3-diamine

N ^1- (4,5-dimethyl-2-nitrophenyl) propane-1,3-diamine (134 mg, 0.60 mmol) was dissolved in MeOH (6 mL) at room temperature, benzaldehyde (64 mg, 0.60 mmol) and AcOH (1 drop) was added. The solution was stirred at rt for 2 h, then NaBH ₃ CN (75 mg, 1.20 mmol) was added in one portion and the resulting solution was stirred at rt for 16 h. The reaction was terminated with H ₂ O (3 drops) and the reaction mixture was evaporated. The crude product was added to silica gel (5 g) dry using DCM and the product was purified by column chromatography (0-10% MeOH in DCM) to give N ¹ -benzyl-N ^3- (4,5- Dimethyl-2-nitrophenyl) propane-1,3-diamine (147 mg, 78%) was obtained as an oily film. LC-MS mlz 314.1 [M + H], retention time 4.96 min.

Step 3: N ^One Preparation of-(3- (benzylamino) propyl) -4,5-dimethylbenzene-1,2-diamine

N ¹ -benzyl-N ^3- (4,5-dimethyl-2-nitrophenyl) propane-1,3-diamine (147 mg, 0.47 mmol) was dissolved in MeOH (15 mL). The reaction vessel was placed under vacuum, filled again with Ar, and the process repeated. Pd / C (50 mg, 10% Pd / C, 3% Pd w / w) was added to the solution and the mixture was cooled to 0 ° C. under Ar. The vessel was placed under vacuum and then refilled with H ₂ (1 atm). The reaction was stirred at 0 ° C. for 16 h, at which time the reaction mixture was placed in vacuo, refilled with Ar, and filtered through celite using MeOH (50 mL) to elute the product. The solvent was evaporated to give N ^1- (3- (benzylamino) propyl) -4,5-dimethylbenzene-1,2-diamine (135 mg, quantitative) as an oil which was used in the next step without further purification. Was

Step 4: Preparation of 10- (3- (benzylamino) propyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetic acid salt

Crude N ^1- (3- (benzylamino) propyl) -4,5-dimethylbenzene-1,2-diamine (0.47 mmol), siloxane monohydrate (79 mg, 0.49 mmol) and boric acid (58 mg, 0.94 mmol) was dissolved in AcOH (10 mL) at room temperature and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness, dissolved in ACN (5 mL) and H ₂ O (5 mL) and purified by preparative HPLC. 56 mg (0.14) of 10- (3- (benzylamino) propyl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione 2,2,2-trifluoroacetate mmol, 30% yield) as a yellow powder.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.15 (t, 2H), 2.47 (s, 3H), 2.52 (s, 3H), 3.11 (m, 2H), 4.15 (t, 2H), 4.72 ( t, 2H), 7.45 (m, 3H), 7.54 (m, 2H), 7.85 (s, 1H), 7.96 (s, 1H), 8.84 (br s, 2H), 11.43 (s, 1H). LC-MS mlz 390.2 [M + H], retention time 2.46 minutes.

Example 48

10-hexyl-7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

Step 1: Preparation of N-hexyl-4,5-dimethyl-2-nitroaniline

N-hexyl-4,5-dimethyl-2-nitroaniline is obtained from 1-bromo-4,5-dimethyl-2-nitrobenzene (230 mg, 1.0 mmol) in N-hexylamine (300 mg, 3.0 mmol). The knit solution was produced by heating at 115 ° C. for 5 hours. The resulting mixture was diluted in DCM (40 mL), washed successively with H ₂ O (40 mL), 1 M HCl (30 mL) and brine (40 mL), dried over Na ₂ SO ₄ , filtered And evaporation gave 235 mg (0.94 mmol, 94% yield) of the product as an orange powder. LC-MS mlz 251.0 [M + H] ⁺ , retention time 5.33 minutes.

Step 2: N ^One Preparation of -hexyl-4,5-dimethylbenzene-1,2-diamine

N ¹ -hexyl-4,5-dimethylbenzene-1,2-diamine was dissolved in Pd / C (10% Pd / C, 4% Pd w / w) and NaBH ₄ (115 mg, 3.0 mmol) in MeOH (10 mL). ) Was produced from N-hexyl-4,5-dimethyl-2-nitroaniline (235 mg, 0.94 mmol) at room temperature under Ar. The reaction was completed within 40 minutes, at which time the reaction mixture was filtered through Celite using MeOH (30 mL) to elute the product. The solvent was then evaporated to give N ¹ -hexyl-4,5-dimethylbenzene-1,2-diamine (quantitative) as a mixture of borate salts, which was used without further purification in the next step.

Step 3: Preparation of 10-hexyl-7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

10-hexyl-7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione is crude N ¹ -hexyl-4,5-dimethylbenzene- ¹ in AcOH (10 mL), It was produced from 2-diamine (0.94 mmol), siloxane monohydrate (158 mg, 0.99 mmol) and boric acid (117 mg, 1.9 mmol) for 3 hours at room temperature. The reaction mixture was evaporated to dryness, dissolved in DCM (30 mL) and H ₂ O (50 mL) and the aqueous phase extracted with DCM (2 × 20 mL). The combined organic portions were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and evaporated to purify by preparative TLC (mobile phase 5% MeOH in DCM). The product was isolated as a light orange powder (122 mg, 39% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91 (t, 3H), 1.37 (m, 4H), 1.53 (m, 2H), 1.85 (quint., 2H), 2.45 (s, 3H), 2.57 (s , 3H), 4.69 (s, 2H), 7.39 (s, 1H), 8.06 (s, 1H), 8.59 (s, 1H). LC-MS mlz 327.1 [M + H] ⁺ , retention time 5.28 minutes.

Example 49

10- (hex-5-en-1-yl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

Step 1: N ^One Preparation of-(hex-5-en-1-yl) -4,5-dimethylbenzene-1,2-diamine

N ^1- (hex-5-en-1-yl) -4,5-dimethylbenzene-1,2-diamine is obtained from 4,5-dimethylbenzene-1,2-diamine in THF (100 ml) (1 g, 7.34 mmol) and a solution of 6-bromohex-1-ene (1.197 g, 7.34 mmol), sodium iodide (2.20 g, 14.68 mmol) and triethylamine (1.485 g, 14.68 mmol) at 60 ° C. for 12 hours. Created by heating. The resulting mixture was diluted with EtOAc (100 mL), washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was added to dryness on silica gel and purified by column chromatography (gradient 0-50% EtOAc) using EtOAc in hexane as eluent. N ^1- (hex-5-en-1-yl) -4,5-dimethylbenzene-1,2-diamine was isolated by evaporation of the appropriate fraction (870 mg, 54% yield). LC-MS mlz 219.1 [M + H], retention time 2.98 min.

Step 2: Preparation of 10- (hex-5-en-1-yl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione

10- (hex-5-en-1-yl) -7,8-dimethylbenzo [g] pteridine-2,4 (3H, 10H) -dione is N ^1- (hex- in AcOH (30 mL) 5-en-1-yl) -4,5-dimethylbenzene-1,2-diamine (830 mg, 3.8 mmol), oxalo monohydrate (608 mg, 3.8 mmol) and boric acid (1.028 g, 3.8 mmol) Produced by stirring at room temperature for 3 hours. The reaction mixture was evaporated to dryness, dissolved in EtOAc (100 mL) and H ₂ O (100 mL), the organic phase washed with brine (2 × 50 mL), dried over Na ₂ SO ₄ , filtered and , Evaporated to a solid, added dry on silica gel and purified by column chromatography (gradient 0-30% EtOAc) using EtOAc in hexane as eluent. The product was isolated as a yellow powder (226 mg, 18% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.66 (m, 2H), 1.90 (m, 2H), 1.20 (t, 2H), 2.48 (s, 3H), 2.59 (s, 3H), 4.73 (br s , 2H), 5.06 (m, 2H), 5.83 (m, 1H), 7.42 (s, 1H), 8.09 (s, 1H), 8.53 (s, 1H). LC-MS mlz 325.0 [M + H] ⁺ , retention time 4.95 minutes.

The compounds of the invention, in particular the compounds set forth in Table 3 below, are disclosed and claimed individually and / or collectively, which generally use procedures similar to those specified in General Procedures 1 and 2 and / or Examples 41-49, above. Can be generated. Appropriate agents, solvents and reaction conditions for these reactions are understood to be used as will be apparent to those skilled in the art.

Claims (36)

A compound of formula Q (i) in free or salt form:
<Formula Q (i)>

In the above formulas,
(i) Alk is C _1-6 alkylene (eg, methylene, ethylene, n-propylene, n-butylene or n-pentylene);
(ii) X is -N (R ₆ ) and A is
-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),
-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, (isoxazol-5-yl) methyl, tetrazolyl, Pyridyls such as pyrid-3-yl, (pyrid-5-yl) methyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl) [wherein the above-alkylaryl ¹ and -alkylhetero aryl alkyl groups of ^1-hydroxy-1, or another aryl group (e.g., phenyl) optionally are substituted, wherein - the ^first and alkyl aryl-alkyl-aryl group and heteroaryl ^{1 1 1} of heteroaryl one or more independently
-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,
-OH,
Heteroaryl ¹ (eg imidazolyl),
HeteroC _3-8 cycloalkyl (eg, morpholinyl),
Aryl ¹ (eg phenyl),
-O-halo-C _1-4 alkyl (eg -OCF ₃ ),
-NO ₂ ,
-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,
Substituted with -SO ₂ -C _1-4 alkyl (eg -SO ₂ -CH ₃ );
-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;
-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);
-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);
-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);
-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);
-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);
-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);
-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;
-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl; or
Para-phenylbenzyl; or
X is a single bond and A is monocyclic heteroaryl ² (eg pyrrolyl, eg pyrrole-1-yl; pyridyl, eg pyrid-2-yl, pyrid-4-yl or pyrid) -3-yl; tetrazolyl, eg 1,2,3,4-tetrazol-1-yl; imidazolyl, eg imidazol-1-yl; or isoxazolyl, eg isoxazole -5-yl), wherein the monocyclic heteroaryl ² is optionally substituted with C _1-4 alkyl (eg methyl); or
X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH _2- , -N (R ₆ ) -CH ₂ CH _2- , -N (R ₆ ) -C (H) (CH ₃ )-or -C (O)-, and
A is C _3-8 cycloalkyl ² (eg, C ₄ cycloalkyl ² or C _5-6 cycloalkyl ² ), wherein at least one carbon atom of said cycloalkyl ² is N, O, S, S (O) ₂ or Optionally and independently substituted with -C (O)-, for example
Cyclobutyl,
Cyclopentyl,
Cyclohexyl,
1-methylcyclohex-1-yl,
Piperidinyl (eg, piperidin-1-yl),
Pyrrolidinyl (e.g., pyrrolidin-1-yl),
Morpholinyl (eg, morpholin-4-yl),
Azapanyl (eg, azapan-1-yl),
Piperazinyl,
2,5-dioxopiperazin-1-yl,
Tetrahydropyranyl (eg, tetrahydropyran-4-yl),
Isoxazolidinyl (isoxazolidin-5-yl),
1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl,
1,1,3-trioxo-1,2,5-thiazolidin-2-yl,
2-oxocyclopentylideneyl,
2-oxooxazolidin-5-yl,
2-oxopyrimidin-1-yl or
2,4-dioxo-imidazolidin-3-yl,
Wherein said cycloalkyl ² is at least one
C _1-4 alkyl (eg methyl),
-C (O) OR ₇ ,
-CH ₂ C (O) OR ₇ ,
-N (R ₆ ) C (O) OR ₇ ,
-OH,
Hydroxy-C _1-4 alkyl (eg hydroxymethyl),
C _1-4 alkoxy (eg methoxy),
-CH ₂ N (R ₆ ) -C (O) OR ₇ ,
² aryl (e.g., phenyl) or aryl ² -C _{1 -4} alkyl (e.g., benzyl) wherein the aryl ² or aryl ^2, wherein the ^second group of the alkyl aryl C _{1 - 4} alkyl optionally substituted with (e. G., Methyl) ], For example 4-methylphenyl, 2-methylphenyl,
Heteroaryl ² (eg 2H-tetrazol-5-yl),
Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl),
-C _1-4 alkyl-N (R ₈ ) (R ₉ ) (eg -methyl-NH ₂ -or -ethyl-NH ₂ ),
C _1-4 alkoxy (eg methoxy),
-C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H) S (O) ₂ -CH ₃ ),
-N (H) -S (O) ₂ -C _1-4 alkyl (e.g., -N (H) -S (O) ₂ -methyl),
-S (O) ₂ -N (R ₈ ) (R ₉ ) (e.g. -S (O) ₂ -NH ₂ ),
-C (O) N (H) CN,
-C (O) N (R ₈ ) (R ₉ ) or
Optionally substituted with —N (R ₈ ) (R ₉ ); or
A is a 7-11 membered fused cycloalkyl-aryl or helical compound wherein at least one carbon atom can be a hetero atom selected from N, O or S, wherein the fused cycloalkyl-aryl or helical group is at least one hydroxy Optionally substituted with C _1-4 alkyl (eg methyl) or oxo (ie ═O)], for example
3,9-diazaspiro [5.5] undecane-3-yl,
3,9-diazaspiro [5.5] undecane-9-day,
(6-oxo-7-oxa-2-azaspiro [4.4] nonan-2-yl),
(9-oxo-8-oxa-3-azaspiro [4.4] nonan-3-yl),
(1-oxo-2,8-diazaspiro [4.5] decane-8-yl),
(2,4-dioxo-3,8-diazaspiro [4.5] decane-8-yl),
Indolinyl (e.g. indolin-1-yl),
Indanyl (eg, indan-1-yl, indan-2-yl or 2-hydroxyindan-1-yl),
Tetralinyl (e.g. tetralin-2-yl, tetralin-1-yl),
Isoindolinyl (e.g. isoindolin-2-yl),
Adamantyl,
3,4-dihydro-1H-isoquinolin-2-yl or 3,4-dihydro-2H-quinolin-1-yl,
1,3,4,5-tetrahydro-2-benzazin-2-yl,
2,3,4,5-tetrahydro-1-benzazin-1-yl,
1,2,4,5-tetrahydro-3-benzazin-3-yl;
(iii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl (eg -O- Cyclopentyl);
(v) R ₄ and R ₅ are
H,
C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),
-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],
Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,
Aryl ² -C _1-4 alkyl, wherein the aryl ² group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;
(vi) R ₆ is H or C _1-4 alkyl (eg methyl);
(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(viii) R ₈ and R ₉ are independently H or C _1-4 alkyl;
(ix) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );
(x) R ₁₁ and R ₁₂ are independently H or C _{1 - 4} alkyl and,
only,
(a) when R ₂ is chloro, Alk is propylene, X is a single bond, and A is pyrrolidin-1-yl, then R ₁ is C _1-8 alkyl (e.g. methyl) or R ₁₀ is- C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ), ie the compound is 8-chloro-10- (3-pyrrolidin-1-ylpropyl) benzo [ g] not pteridine-2,4-dione;
(b) The compound is 10- [3- (3,6-dioxo-1,4-cyclohexadien-1-yl) propyl) -3,7,8-trimethyl-benzo [g] pteridine-2 , 4- (3H, 10H) -dione;
(c) A is not furinyl, for example the compound is optionally substituted 10- [2- (9H-purin-9-yl) ethyl]-, 10- [3- (9H-purin-9-yl) Propyl]-or 10- [6- (9H-purin-9-yl) hexyl] -7,8-dimethyl-benzo [g] pteridine-2,4- (3H, 10H) -dione;
(d) A is not indol-3-yl, for example the compound is 10- [3- (1H-indol-3-yl) ethyl]-or 10- [3- (1H-indol-3-yl) Propyl] -7,8-dimethyl-benzo [g] pteridine-2,4- (3H, 10H) -dione;
(e) -Alk-XA is not 2- (2-oxocyclopentylidene) ethyl. The compound of claim 1, wherein the compound is a compound of formula QI (i) in free or salt form:
<Formula QI (i)>

In the above formulas,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene, n-butylene or n-pentylene);
(ii) X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH _2- , -N (R ₆ ) -CH ₂ CH _2- , -N (R ₆ ) -C (H ) (CH ₃ )-or -C (O)-, and
A is —C _3-8 cycloalkyl ² (eg, C ₄ cycloalkyl ² or C _5-6 cycloalkyl ² ), wherein at least one carbon atom of said cycloalkyl ² is N, O, S, S (O) ₂ Or optionally and independently substituted with -C (O)-, for example
Cyclobutyl,
Cyclopentyl,
Cyclohexyl,
1-methylcyclohex-1-yl,
Piperidinyl (eg, piperidin-1-yl),
Pyrrolidinyl (e.g., pyrrolidin-1-yl),
Morpholinyl (eg, morpholin-4-yl),
Azapanyl (eg, azapan-1-yl),
Piperazinyl,
2,5-dioxopiperazin-1-yl,
Tetrahydropyranyl (eg, tetrahydropyran-4-yl),
Isoxazolidinyl (isoxazolidin-5-yl),
1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl,
1,1,3-trioxo-1,2,5-thiazolidin-2-yl,
2-oxocyclopentylideneyl,
2-oxooxazolidin-5-yl,
2-oxopyrimidin-1-yl or
2,4-dioxo-imidazolidin-3-yl);
Wherein said cycloalkyl ² is at least one
C _1-4 alkyl (eg methyl),
-C (O) OR ₇ ,
-CH ₂ C (O) OR ₇ ,
-N (R ₆ ) C (O) OR ₇ ,
-OH,
Hydroxy-C _1-4 alkyl (eg hydroxymethyl),
C _1-4 alkoxy (eg methoxy),
-CH ₂ N (R ₆ ) -C (O) OR ₇ ,
² aryl (e.g., phenyl) or aryl ² -C _1-4 alkyl (e.g., benzyl) wherein the aryl ² or aryl ^2-aryl wherein the alkyl group is optionally substituted by ^two C _1-4 alkyl (e.g., methyl) ], For example 4-methylphenyl, 2-methylphenyl;
Heteroaryl ² (eg 2H-tetrazol-5-yl),
Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl),
-C _1-4 alkyl-N (R ₈ ) (R ₉ ) (eg -methyl-NH ₂ -or -ethyl-NH ₂ ),
C _1-4 alkoxy (eg methoxy),
-C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H) S (O) ₂ -CH ₃ ),
-N (H) -S (O) ₂ -C _1-4 alkyl (e.g., -N (H) -S (O) ₂ -methyl),
-S (O) ₂ -N (R ₈ ) (R ₉ ) (e.g. -S (O) ₂ -NH ₂ ),
-C (O) N (H) CN,
-C (O) N (R ₈ ) (R ₉ ) or
Optionally substituted with —N (R ₈ ) (R ₉ ); or
A is a 7-11 membered fused cycloalkyl-aryl or helical compound wherein at least one carbon atom can be a hetero atom selected from N, O or S, wherein the fused cycloalkyl-aryl or helical group is at least one hydroxy Optionally substituted with C _1-4 alkyl (eg methyl) or oxo (ie ═O)], for example
3,9-diazaspiro [5.5] undecane-3-yl,
3,9-diazaspiro [5.5] undecane-9-day,
(6-oxo-7-oxa-2-azaspiro [4.4] nonan-2-yl),
(9-oxo-8-oxa-3-azaspiro [4.4] nonan-3-yl),
(1-oxo-2,8-diazaspiro [4.5] decane-8-yl),
(2,4-dioxo-3,8-diazaspiro [4.5] decane-8-yl),
Indolinyl (e.g. indolin-1-yl),
Indanyl (eg, indan-1-yl, indan-2-yl or 2-hydroxyindan-1-yl),
Tetralinyl (e.g. tetralin-2-yl, tetralin-1-yl),
Isoindolinyl (e.g. isoindolin-2-yl),
Adamantyl,
3,4-dihydro-1H-isoquinolin-2-yl or 3,4-dihydro-2H-quinolin-1-yl,
1,3,4,5-tetrahydro-2-benzazin-2-yl,
2,3,4,5-tetrahydro-1-benzazin-1-yl,
1,2,4,5-tetrahydro-3-benzazin-3-yl,
(ii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iii) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl (eg -O- Cyclopentyl);
(v) R ₄ and R ₅ are
H,
C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),
-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],
Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,
Aryl ² -C _1-4 alkyl, wherein the aryl ² group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;
(vi) R ₆ is H or C _1-4 alkyl (eg methyl);
(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(viii) R ₈ and R ₉ are independently H or C _1-4 alkyl;
(ix) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ). The compound of claim 1, wherein the compound is a compound of formula Q-II (i) in free or salt form:
<Formula Q-II (i)>

In the above formulas,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene, n-butylene or n-pentylene);
(ii) X is a single bond and A is monocyclic heteroaryl ² (eg pyrrolyl, eg pyrrole-1-yl; pyridyl, eg pyrid-2-yl, pyrid-4-yl Or pyrid-3-yl; tetrazolyl, eg 1,2,3,4-tetrazol-1-yl; imidazolyl, eg imidazol-1-yl; or isoxazolyl, eg g. isoxazol-5-yl), wherein said heteroaryl ² is one or more C _{1 - 4} and optionally substituted with alkyl (e.g., methyl);
(iii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl ² (eg -O -Cyclopentyl);
(v) R ₄ and R ₅ are
H,
C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),
-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],
Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,
Aryl ² -C _1-4 alkyl, wherein the aryl group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;
(vi) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(vii) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ). The compound of claim 1, wherein the compound is a compound of formula Q-III (i) in free or salt form:
<Formula Q-III (i)>

In the above formulas,
(i) Alk is C _1-6 alkylene (eg, methylene, ethylene, n-propylene, n-butylene or n-pentylene);
(ii) X is -N (R ₆ ) and A is
-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),
-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, (isoxazol-5-yl) methyl, tetrazolyl, Pyridyls such as pyrid-3-yl, (pyrid-5-yl) methyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl) [wherein the above-alkylaryl ¹ and -alkylhetero aryl alkyl groups of ^1-hydroxy-1, or another aryl group (e.g., phenyl) optionally are substituted, wherein - the ^first and alkyl aryl-alkyl-aryl group and heteroaryl ^{1 1 1} of heteroaryl one or more
-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,
-OH,
Heteroaryl ¹ (eg imidazolyl),
HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),
Aryl ¹ (eg phenyl),
-O-halo-C _1-4 alkyl (eg -OCF ₃ ),
-NO ₂ ,
-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,
Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );
-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;
-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);
-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);
-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);
-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);
-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);
-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);
-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;
-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl;
Para-phenylbenzyl;
(iii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl ² (eg -O -Cyclopentyl);
(v) R ₄ and R ₅ are
H,
C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),
-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],
Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,
Aryl ² -C _1-4 alkyl, wherein the aryl group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;
(vi) R ₆ is H or C _1-4 alkyl (eg methyl);
(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(viii) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );
(ix) R ₁₁ and R ₁₂ are independently H or C _1-4 alkyl. The compound of claim 1, wherein the compound is a compound of formula Q-IV (i) in free or salt form:
<Q-IV (i)>

In the above formulas,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene);
(ii) X is a single bond and A is pyrrolyl such as pyrrole-1-yl or imidazolyl such as imidazol-1-yl; or
X is a single bond, and A is pyrrolidinyl (eg pyrrolidin-1-yl) or piperidi optionally substituted with another aryl (eg phenyl) or aryl-C _1-4 alkyl (eg benzyl) Nil (eg piperidin-1-yl); or
X is -N (R ₆ )-and A is tetralinyl (eg, tetralin-2-yl);
(iii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl);
(v) R ₆ is H or C _1-4 alkyl (eg methyl);
(vi) R ₁₀ is H. The compound of claim 1, wherein the compound is a compound of formula QV (i) in free or salt form:
<Formula QV (i)>

In the above formulas,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene or n-propylene);
(ii) X is a single bond and A is pyrrolyl optionally substituted with another aryl (e.g. phenyl) or aryl-C _1-4 alkyl (e.g. benzyl), e.g. pyrrole-1-yl, pyrroli Dinil (eg pyrrolidin-1-yl) or piperidinyl (eg piperidin-1-yl);
(iii) R ₁ is C _1-8 alkyl (eg methyl);
(iv) R ₂ is C _1-4 alkyl (eg methyl);
(v) R ₁₀ is H. The compound of claim 1, wherein the compound is a compound of formula I (B) in free or salt form:
<Formula I (B)>

In the above formulas,
(i) Alk is C _1-2 alkylene (eg methylene or ethylene);
(ii) X is -N (R ₆ )-,
(iii) A is
-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),
-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, tetrazolyl, pyridyl, indolyl, 1,2, 5-oxadiazolyl, pyrrolyl) wherein the alkyl group of the -alkylaryl ¹ and -alkylheteroaryl ¹ is optionally substituted with hydroxy or another aryl (e.g. phenyl) and the -alkylaryl ¹ and -alkylhetero aryl ^{1 1} aryl and heteroaryl ¹ group is at least one
-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,
-OH,
Heteroaryl ¹ (eg imidazolyl),
HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),
Aryl ¹ (eg phenyl),
-O-halo-C _1-4 alkyl (eg -OCF ₃ ),
-NO ₂ ,
-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,
Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );
-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;
-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);
-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);
-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);
-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);
-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);
-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);
-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;
-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl;
Para-phenylbenzyl;
(iv) R ₁ is H or C _1-4 alkyl (eg methyl);
(v) R ₂ is selected from the group consisting of H, C _1-4 alkyl (eg methyl) and —OC _3-8 cycloalkyl ¹ (eg —O-cyclopentyl);
(vi) R ₆ is H or C _1-4 alkyl (eg methyl);
(vii) R ₁₁ and R ₁₂ are independently H or C _1-4 alkyl (eg methyl). 8. The compound according to claim 1, wherein the compound is in the form of a free or salt form. Formula Q.35, Q.36, Q.37, Q.38, Q.39, Q.40 or Q.41 A compound selected from any of the compounds described. A compound of formula I (A) (i) in free, salt or prodrug form:
<Formula I (A) (i)>

In the above formulas,
(i) Alk is C _1-6 alkylene (eg methylene or ethylene);
(ii) X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH ₂ -or -C (O)-;
(iii) A is monocyclic heteroaryl (eg, pyrid-4-yl or pyrid-3-yl) or C _5-6 cycloalkyl, wherein at least one carbon atom of said cycloalkyl is N, O, S or Optionally and independently substituted with —C (O) — (eg piperidinyl (eg piperidin-1-yl), pyrrolidinyl (eg pyrrolidin-1-yl), pipera Genyl (eg 2,5-dioxopiperazin-1-yl), isoxazolidinyl (isoxazolidin-5-yl), 1,1-dioxo-1,4-thiazinan-4-yl , C _3-8 cycloalkyl (eg cyclopentyl, cyclohexyl or 2-oxocyclopentylidene), 2-oxopyrimidin-1-yl or 2,4-dioxo-imidazol-3-yl) Wherein the heteroaryl and cycloalkyl are one or more of -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (eg hydroxymethyl), -CH ₂ N (R ₆ ) -C (O) OR ₇ , heteroaryl (eg 2H-tetrazol-5-yl), heteroaryl-C _1-4 Alkyl (eg 2H-tetrazol-5-yl-methyl), amine C _1-4 alkyl (eg amine-ethyl), C _1-4 alkoxy (eg methoxy), -C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (eg -C (O) N (H) S (O) Independently optionally substituted with ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ );
(iv) R ₁ is H or C _1-8 alkyl (eg methyl);
(v) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), —N (R ₄ ) (R ₅ );
(vi) R ₄ and R ₅ are H, C _3-7 cycloalkyl (eg cyclopropyl or cyclopentyl), -C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is -OH, -C (O) OR ₇ , optionally substituted with one or more groups selected from aryl (eg 4-fluorophenyl) optionally substituted with halo];
(vii) R ₆ is H or C _1-4 alkyl (eg methyl);
(viii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(ix) R ₈ and R ₉ are independently H or C _1-4 alkyl;
(x) R ₁₀ is H or -C _{1 - 4} alkyl, -OC (O) CH ₃ (for _{example, -CH 2 OC (O) CH} 3) , and
Provided that when R ₂ is chloro, Alk is propylene, X is a single bond, and A is pyrrolidin-1-yl, then R ₁ is C _1-8 alkyl (e.g. methyl) or R ₁₀ is -C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ). A compound of formula II (A) in free, salt or prodrug form:
<Formula II (A)>

In the above formulas,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene, pentylene);
(ii) Y is -N (R ₆ ) -C (O)-or -C (O) -N (R ₆ )-;
(iii) A is at least one -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (Eg hydroxymethyl), -CH ₂ N (R ₆ ) -C (O) OR ₇ , heteroaryl (eg 2H-tetrazol-5-yl), heteroaryl-C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl), amine C _1-4 alkyl (eg amine-ethyl), C _1-4 alkoxy (eg methoxy), -C (O) N (R ₆ ) -S (O) heteroaryl optionally substituted with ₂ -C _1-4 alkyl (eg -C (O) N (H) S (O) ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ ) (eg , Pyrid-3-yl);
(iv) R ₁ is H or C _1-8 alkyl (eg methyl);
(v) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), —N (R ₄ ) (R ₅ );
(vi) R ₄ and R ₅ are independently selected from H, C _3-7 cycloalkyl (eg cyclopropyl or cyclopentyl), —C _1-4 alkyl (eg methyl or ethyl), wherein the alkyl is Optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ , aryl optionally substituted with halo (eg, 4-fluorophenyl);
(vii) R ₆ is H or C _1-4 alkyl (eg methyl);
(viii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(ix) R ₈ and R ₉ are independently H, C _1-4 alkyl;
(x) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ ). The compound of claim 10, wherein the compound is selected from any one described as Formula 2.8 in free, pharmaceutically acceptable salt form. A compound of formula II (B) in free or salt form:
<Formula II (B)>

In the above formulas,
(i) R ₁ is H or C _1-4 alkyl (eg methyl);
(ii) R ₂ is selected from the group consisting of H, C _1-4 alkyl (eg methyl) and —OC _3-8 cycloalkyl ¹ (eg —O-cyclopentyl);
(iii) Y is

It is selected from the group consisting of. The compound of claim 12, wherein the compound of Formula II (B) is selected from any of the compounds described in Formula 3.51, 3.52, 3.53 or 3.54 in free or salt form. The compound of claim 12 or 13, wherein the compound of Formula II (B) is selected from any of the following formulas which are in free or salt form:

A compound of formula III (B) in free or salt form:
<Formula III (B)>

In the above formulas,
(i) R ₁ is H or C _1-4 alkyl (eg methyl);
(ii) R ₂ is selected from the group consisting of H, C _1-4 alkyl (eg methyl) and —OC _3-8 cycloalkyl (eg —O-cyclopentyl);
(iii) R ₄ is benzyl;
(iv) R ₅ is aryl ¹ -C _0-4 alkyl (eg phenyl, benzyl, phenylpropyl), hydroxyC _1-4 alkyl (hydroxybutyl), C _1-4 alkyl (eg n-butyl) , C _3-8 cycloalkyl ¹ (eg cyclopentyl), wherein R ₅ is optionally substituted with one or more hydroxy or C _1-4 alkyl (eg methyl); or
(v) R ₄ is H and R ₅ is 1,2-diphenylethyl or 1-hydroxy-2-hydroxymethyl-2-phenyl (-C (H) (CH ₂ OH) -C (H) (OH) -C ₆ H ₅ ). The compound of claim 15, wherein the compound of Formula III (B) is selected from any of the following formulas in free or salt form:

A compound of formula IV (B) selected from any of the following formulas in free or salt form:

A compound of formula V (B) selected from any of the following formulas in free or salt form:

Treating a bacterial infection comprising administering to a patient in need thereof an effective amount of a compound selected from any of the following a) compounds to i) compounds in free or pharmaceutically acceptable salt form: Or preventive measures:
a) a compound of formula Q:
<Formula Q>

{In the above formula,
(i) Alk is C _1-6 alkylene (eg, methylene, ethylene, n-propylene, n-butylene or n-pentylene);
(ii) X is -N (R ₆ ) and A is
-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),
-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, (isoxazol-5-yl) methyl, tetrazolyl, Pyridyls such as pyrid-3-yl, (pyrid-5-yl) methyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl) [wherein the above-alkylaryl ¹ and -alkylhetero aryl alkyl groups of ^1-hydroxy-1, or another aryl group (e.g., phenyl) optionally are substituted, wherein - the ^first and alkyl aryl-alkyl-aryl group and heteroaryl ^{1 1 1} of heteroaryl one or more
-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,
-OH,
Heteroaryl ¹ (eg imidazolyl),
HeteroC _3-8 cycloalkyl (eg, morpholinyl),
Aryl ¹ (eg phenyl),
-O-halo-C _1-4 alkyl (eg -OCF ₃ ),
-NO ₂ ,
-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,
Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );
-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;
-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);
-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);
-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);
-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);
-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);
-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);
-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;
-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl; or
Para-phenylbenzyl; or
X is a single bond and A is monocyclic heteroaryl ² (eg pyrrolyl, eg pyrrole-1-yl; pyridyl, eg pyrid-2-yl, pyrid-4-yl or pyrid) -3-yl; tetrazolyl, eg 1,2,3,4-tetrazol-1-yl; imidazolyl, eg imidazol-1-yl; or isoxazolyl, eg isoxazole -5-yl), wherein the monocyclic heteroaryl ² is optionally substituted with C _1-4 alkyl (eg methyl); or
X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH _2- , -N (R ₆ ) -CH ₂ CH _2- , -N (R ₆ ) -C (H) (CH ₃ )-or -C (O)-, and
A is C _3-8 cycloalkyl ² (eg, C ₄ cycloalkyl ² or C _5-6 cycloalkyl ² ), wherein at least one carbon atom of said cycloalkyl ² is N, O, S, S (O) ₂ or Optionally and independently substituted with -C (O)-, for example
Cyclobutyl,
Cyclopentyl,
Cyclohexyl,
1-methylcyclohex-1-yl,
Piperidinyl (eg, piperidin-1-yl),
Pyrrolidinyl (e.g., pyrrolidin-1-yl),
Morpholinyl (eg, morpholin-4-yl),
Azapanyl (eg, azapan-1-yl),
Piperazinyl,
2,5-dioxopiperazin-1-yl,
Tetrahydropyranyl (eg, tetrahydropyran-4-yl),
Isoxazolidinyl (isoxazolidin-5-yl),
1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl,
1,1,3-trioxo-1,2,5-thiazolidin-2-yl,
2-oxocyclopentylideneyl,
2-oxooxazolidin-5-yl,
2-oxopyrimidin-1-yl or
2,4-dioxo-imidazolidin-3-yl,
Wherein said cycloalkyl ² is at least one
C _1-4 alkyl (eg methyl),
-C (O) OR ₇ ,
-CH ₂ C (O) OR ₇ ,
-N (R ₆ ) C (O) OR ₇ ,
-OH,
Hydroxy-C _1-4 alkyl (eg hydroxymethyl),
C _1-4 alkoxy (eg methoxy),
-CH ₂ N (R ₆ ) -C (O) OR ₇ ,
² aryl (e.g., phenyl) or aryl ² -C _1-4 alkyl (e.g., benzyl) wherein the aryl ² or aryl ^2-aryl wherein the alkyl group is optionally substituted by ^two C _1-4 alkyl (e.g., methyl) ], For example 4-methylphenyl, 2-methylphenyl,
Heteroaryl ² (eg 2H-tetrazol-5-yl),
Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl),
-C _1-4 alkyl-N (R ₈ ) (R ₉ ) (eg -methyl-NH ₂ -or -ethyl-NH ₂ ),
C _1-4 alkoxy (eg methoxy),
-C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H) S (O) ₂ -CH ₃ ),
-N (H) -S (O) ₂ -C _1-4 alkyl (e.g., -N (H) -S (O) ₂ -methyl),
-S (O) ₂ -N (R ₈ ) (R ₉ ) (e.g. -S (O) ₂ -NH ₂ ),
-C (O) N (H) CN,
-C (O) N (R ₈ ) (R ₉ ) or
Optionally substituted with —N (R ₈ ) (R ₉ ); or
A is a 7-11 membered fused cycloalkyl-aryl or helical compound wherein at least one carbon atom can be a hetero atom selected from N, O or S, wherein the fused cycloalkyl-aryl or helical group is at least one hydroxy Optionally substituted with C _1-4 alkyl (eg methyl) or oxo (ie ═O)], for example
3,9-diazaspiro [5.5] undecane-3-yl,
3,9-diazaspiro [5.5] undecane-9-day,
(6-oxo-7-oxa-2-azaspiro [4.4] nonan-2-yl),
(9-oxo-8-oxa-3-azaspiro [4.4] nonan-3-yl),
(1-oxo-2,8-diazaspiro [4.5] decane-8-yl),
(2,4-dioxo-3,8-diazaspiro [4.5] decane-8-yl),
Indolinyl (e.g. indolin-1-yl),
Indanyl (eg, indan-1-yl, indan-2-yl or 2-hydroxyindan-1-yl),
Tetralinyl (e.g. tetralin-2-yl, tetralin-1-yl),
Isoindolinyl (e.g. isoindolin-2-yl),
Adamantyl,
3,4-dihydro-1H-isoquinolin-2-yl or 3,4-dihydro-2H-quinolin-1-yl,
1,3,4,5-tetrahydro-2-benzazin-2-yl,
2,3,4,5-tetrahydro-1-benzazin-1-yl,
1,2,4,5-tetrahydro-3-benzazin-3-yl;
(iii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl (eg -O- Cyclopentyl);
(v) R ₄ and R ₅ are
H,
C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),
-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],
Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,
Aryl ² -C _1-4 alkyl, wherein the aryl ² group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;
(vi) R ₆ is H or C _1-4 alkyl (eg methyl);
(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(viii) R ₈ and R ₉ are independently H or C _1-4 alkyl;
(ix) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );
(x) R ₁₁ and R ₁₂ are independently H or C _1-4 alkyl;
b) a compound of formula QI:
<Formula QI>

{In the above formula,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene, n-butylene or n-pentylene);
(ii) X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH _2- , -N (R ₆ ) -CH ₂ CH _2- , -N (R ₆ ) -C (H ) (CH ₃ )-or -C (O)-, and
A is —C _3-8 cycloalkyl ² (eg, C ₄ cycloalkyl ² or C _5-6 cycloalkyl ² ), wherein at least one carbon atom of said cycloalkyl ² is N, O, S, S (O) ₂ Or optionally and independently substituted with -C (O)-, for example
Cyclobutyl,
Cyclopentyl,
Cyclohexyl,
1-methylcyclohex-1-yl,
Piperidinyl (eg, piperidin-1-yl),
Pyrrolidinyl (e.g., pyrrolidin-1-yl),
Morpholinyl (eg, morpholin-4-yl),
Azapanyl (eg, azapan-1-yl),
Piperazinyl,
2,5-dioxopiperazin-1-yl,
Tetrahydropyranyl (eg, tetrahydropyran-4-yl),
Isoxazolidinyl (isoxazolidin-5-yl),
1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl,
1,1,3-trioxo-1,2,5-thiazolidin-2-yl,
2-oxocyclopentylideneyl,
2-oxooxazolidin-5-yl,
2-oxopyrimidin-1-yl or
2,4-dioxo-imidazolidin-3-yl;
Wherein said cycloalkyl ² is at least one
C _1-4 alkyl (eg methyl),
-C (O) OR ₇ ,
-CH ₂ C (O) OR ₇ ,
-N (R ₆ ) C (O) OR ₇ ,
-OH,
Hydroxy-C _1-4 alkyl (eg hydroxymethyl),
C _1-4 alkoxy (eg methoxy),
-CH ₂ N (R ₆ ) -C (O) OR ₇ ,
² aryl (e.g., phenyl) or aryl ² -C _1-4 alkyl (e.g., benzyl) wherein the aryl ² or aryl ^2-aryl wherein the alkyl group is optionally substituted by ^two C _1-4 alkyl (e.g., methyl) ], For example 4-methylphenyl, 2-methylphenyl;
Heteroaryl ² (eg 2H-tetrazol-5-yl),
Heteroaryl ² -C _1-4 alkyl (eg 2H-tetrazol-5-yl-methyl),
-C _1-4 alkyl-N (R ₈ ) (R ₉ ) (eg -methyl-NH ₂ -or -ethyl-NH ₂ ),
C _1-4 alkoxy (eg methoxy),
-C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (e.g., -C (O) N (H) S (O) ₂ -CH ₃ ),
-N (H) -S (O) ₂ -C _1-4 alkyl (e.g., -N (H) -S (O) ₂ -methyl),
-S (O) ₂ -N (R ₈ ) (R ₉ ) (e.g. -S (O) ₂ -NH ₂ ),
-C (O) N (H) CN,
-C (O) N (R ₈ ) (R ₉ ) or
Optionally substituted with —N (R ₈ ) (R ₉ ); or
A is a 7-11 membered fused cycloalkyl-aryl or helical compound wherein at least one carbon atom can be a hetero atom selected from N, O or S, wherein the fused cycloalkyl-aryl or helical group is at least one hydroxy Optionally substituted with C _1-4 alkyl (eg methyl) or oxo (ie ═O)], for example
3,9-diazaspiro [5.5] undecane-3-yl,
3,9-diazaspiro [5.5] undecane-9-day,
(6-oxo-7-oxa-2-azaspiro [4.4] nonan-2-yl),
(9-oxo-8-oxa-3-azaspiro [4.4] nonan-3-yl),
(1-oxo-2,8-diazaspiro [4.5] decane-8-yl),
(2,4-dioxo-3,8-diazaspiro [4.5] decane-8-yl),
Indolinyl (e.g. indolin-1-yl),
Indanyl (eg, indan-1-yl, indan-2-yl or 2-hydroxyindan-1-yl),
Tetralinyl (e.g. tetralin-2-yl, tetralin-1-yl),
Isoindolinyl (e.g. isoindolin-2-yl),
Adamantyl,
3,4-dihydro-1H-isoquinolin-2-yl or 3,4-dihydro-2H-quinolin-1-yl,
1,3,4,5-tetrahydro-2-benzazin-2-yl,
2,3,4,5-tetrahydro-1-benzazin-1-yl,
1,2,4,5-tetrahydro-3-benzazin-3-yl,
(ii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iii) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl (eg -O- Cyclopentyl);
(v) R ₄ and R ₅ are
H,
C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),
-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],
Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,
Aryl ² -C _1-4 alkyl, wherein the aryl ² group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;
(vi) R ₆ is H or C _1-4 alkyl (eg methyl);
(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(viii) R ₈ and R ₉ are independently H or C _1-4 alkyl;
(ix) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );
c) a compound of formula Q-II:
<Formula Q-II>

{In the above formula,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene, n-butylene or n-pentylene);
(ii) X is a single bond and A is monocyclic heteroaryl ² (eg pyrrolyl, eg pyrrole-1-yl; pyridyl, eg pyrid-2-yl, pyrid-4-yl Or pyrid-3-yl; tetrazolyl, eg 1,2,3,4-tetrazol-1-yl; imidazolyl, eg imidazol-1-yl; or isoxazolyl, eg g. isoxazol-5-yl), wherein said heteroaryl ² is one or more C _{1 - 4} and optionally substituted with alkyl (e.g., methyl);
(iii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl ² (eg -O -Cyclopentyl);
(v) R ₄ and R ₅ are
H,
C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),
-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],
Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,
Aryl ² -C _1-4 alkyl, wherein the aryl group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;
(vi) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(vii) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );
d) a compound of formula Q-III:
<Formula Q-III>

{In the above formula,
(i) Alk is C _1-6 alkylene (eg, methylene, ethylene, n-propylene, n-butylene or n-pentylene);
(ii) X is -N (R ₆ ) and A is
-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),
-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, (isoxazol-5-yl) methyl, tetrazolyl, Pyridyls such as pyrid-3-yl, (pyrid-5-yl) methyl, indolyl, 1,2,5-oxadiazolyl, pyrrolyl) [wherein the above-alkylaryl ¹ and -alkylhetero aryl alkyl groups of ^1-hydroxy-1, or another aryl group (e.g., phenyl) optionally are substituted, wherein - the ^first and alkyl aryl-alkyl-aryl group and heteroaryl ^{1 1 1} of heteroaryl one or more
-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,
-OH,
Heteroaryl ¹ (eg imidazolyl),
HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),
Aryl ¹ (eg phenyl),
-O-halo-C _1-4 alkyl (eg -OCF ₃ ),
-NO ₂ ,
-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,
Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );
-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;
-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);
-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);
-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);
-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);
-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);
-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);
-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;
-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl;
Para-phenylbenzyl;
(iii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), -N (R ₄ ) (R ₅ ) or -OC _3-8 cycloalkyl ² (eg -O -Cyclopentyl);
(v) R ₄ and R ₅ are
H,
C _3-7 cycloalkyl ² (eg cyclopropyl or cyclopentyl),
-C _1-4 alkyl (eg methyl or ethyl), wherein said alkyl is optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ ],
Aryl ² (eg 4-fluorophenyl) optionally substituted with halo,
Aryl ² -C _1-4 alkyl, wherein the aryl group is optionally substituted with halo (eg fluoro); for example independently from 4-fluorophenylethyl;
(vi) R ₆ is H or C _1-4 alkyl (eg methyl);
(vii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(viii) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );
(ix) R ₁₁ and R ₁₂ are independently H or C _1-4 alkyl;
e) a compound of formula Q-IV:
<Formula Q-IV>

{In the above formula,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene, n-propylene);
(ii) X is a single bond and A is pyrrolyl such as pyrrole-1-yl or imidazolyl such as imidazol-1-yl; or
X is a single bond, and A is pyrrolidinyl (eg pyrrolidin-1-yl) or piperidi optionally substituted with another aryl (eg phenyl) or aryl-C _1-4 alkyl (eg benzyl) Nil (eg piperidin-1-yl); or
X is -N (R ₆ )-and A is tetralinyl (eg, tetralin-2-yl);
(iii) R ₁ is H or C _1-8 alkyl (eg methyl);
(iv) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl);
(v) R ₆ is H or C _1-4 alkyl (eg methyl);
(vi) R ₁₀ is H};
f) a compound of formula QV:
<Formula QV>

{In the above formula,
(i) Alk is C _1-6 alkylene (eg methylene, ethylene or n-propylene);
(ii) X is a single bond and A is pyrrolyl optionally substituted with another aryl (e.g. phenyl) or aryl-C _1-4 alkyl (e.g. benzyl), e.g. pyrrole-1-yl, pyrroli Dinil (eg pyrrolidin-1-yl) or piperidinyl (eg piperidin-1-yl);
(iii) R ₁ is C _1-8 alkyl (eg methyl);
(iv) R ₂ is C _1-4 alkyl (eg methyl);
(v) R ₁₀ is H};
g) a compound of formula I (A)
<Formula I (A)>

{In the above formula,
(i) Alk is C _1-6 alkylene (eg methylene or ethylene);
(ii) X is a single bond, -N (R ₆ )-, -N (R ₆ ) -CH ₂ -or -C (O)-;
(iii) A is a monocyclic heteroaryl (eg, pyrid-4-yl or pyrid-3-yl) or C _5-6 cycloalkyl, wherein at least one carbon atom of said cycloalkyl is N, O, S or Optionally and independently substituted with -C (O)-(eg piperidinyl (eg piperidin-1-yl), pyrrolidinyl (eg pyrrolidin-1-yl), pipera Genyl (eg 2,5-dioxopiperazin-1-yl), isoxazolidinyl (isoxazolidin-5-yl), 1,1-dioxo-1,4-thiazinan-4-yl , C _3-8 cycloalkyl (eg cyclopentyl, cyclohexyl or 2-oxocyclopentylidene), 2-oxopyrimidin-1-yl or 2,4-dioxo-imidazol-3-yl) Wherein the heteroaryl and cycloalkyl are one or more of -C (O) OR ₇ , -CH ₂ C (O) OR ₇ , -N (R ₆ ) C (O) OR ₇ , -OH, hydroxy-C _1-4 alkyl (eg hydroxymethyl), -CH ₂ N (R ₆ ) -C (O) OR ₇ , heteroaryl (eg 2H-tetrazol-5-yl), heteroaryl-C _1-4 Alkyl (eg 2H-tetrazol-5-yl-methyl), amine C _1-4 alkyl (eg amine-ethyl), C _1-4 alkoxy (eg methoxy), -C (O) N (R ₆ ) -S (O) ₂ -C _1-4 alkyl (eg -C (O) N (H) S (O) Independently optionally substituted with ₂ -CH ₃ ) or -N (R ₈ ) (R ₉ );
(iv) R ₁ is H or C _1-8 alkyl (eg methyl);
(v) R ₂ is H, halo (eg chloro), C _1-4 alkyl (eg methyl), —N (R ₄ ) (R ₅ );
(vi) R ₄ and R ₅ are independently selected from H, C _3-7 cycloalkyl (eg cyclopropyl or cyclopentyl), -C _1-4 alkyl (eg methyl or ethyl), wherein the alkyl is Optionally substituted with one or more groups selected from -OH, -C (O) OR ₇ , aryl optionally substituted with halo (eg, 4-fluorophenyl);
(vii) R ₆ is H or C _1-4 alkyl (eg methyl);
(viii) R ₇ is H, C _1-4 alkyl (eg methyl, ethyl or tert-butyl), —CH ₂ OC (O) CH ₃ ;
(ix) R ₈ and R ₉ are independently H or C _1-4 alkyl;
(x) R ₁₀ is H or —C _1-4 alkyl-OC (O) CH ₃ (eg, —CH ₂ OC (O) CH ₃ );
h) a compound of formula (I)
<Formula I (B)>

{In the above formula,
(i) Alk is C _1-2 alkylene (eg methylene or ethylene);
(ii) X is -N (R ₆ )-,
(iii) A is
-C _1-4 alkyl-N (R ₁₁ ) (R ₁₂ ),
-C _0-4 alkyl-aryl ¹ (eg phenyl, naphthyl, benzyl) or -C _0-4 alkyl-heteroaryl ¹ (eg isoxazolyl, tetrazolyl, pyridyl, indolyl, 1,2, 5-oxadiazolyl, pyrrolyl) wherein the alkyl group of the -alkylaryl ¹ and -alkylheteroaryl ¹ is optionally substituted with hydroxy or another aryl (e.g. phenyl) and the -alkylaryl ¹ and -alkylhetero aryl ^{1 1} aryl and heteroaryl ¹ group is at least one
-N (R _a ) -C (O) -C _1-4 alkyl (eg, -NHC (O) CH ₃ ), where R _a is H or C _1-4 alkyl,
-OH,
Heteroaryl ¹ (eg imidazolyl),
HeteroC _3-8 cycloalkyl ¹ (eg, morpholinyl),
Aryl ¹ (eg phenyl),
-O-halo-C _1-4 alkyl (eg -OCF ₃ ),
-NO ₂ ,
-N (R _a ) (R _b ), where R _a is H or C _1-4 alkyl and R _b is C _1-4 alkyl,
Independently substituted with -SO ₂ -C _1-4 alkyl (eg, -SO ₂ -CH ₃ );
-C _0-4 alkyl-pyridyl (eg, 2-hydroxypyrid-4-ylmethyl or 2-hydroxypyrid-3-yl) substituted with one or more hydroxy;
-C _0-4 alkyl-benzotriazolyl (eg, 1H-benzotriazol-5-yl);
-C _0-4 alkyl-indolyl (eg, -indol-5-ylmethyl, indol-2-ylmethyl, indol-3-ylethyl);
-C _0-4 alkyl-tetrazolyl (eg, 1,2,3,5-tetrazol-4-ylethyl);
-C _0-4 alkyl-oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl);
-C _0-4 alkyl-benzodioxolyl (eg, 1,3-benzodioxol-5-ylmethyl);
-C _0-4 alkyl-benzimidazolyl optionally substituted with -C _0-4 alkyl (eg 1-methylbenzimidazol-2-ylmethyl, benzimidazol-5-ylmethyl);
-C _0-4 alkyl-imidazolyl (eg 1-methyl-imidazol-5-ylmethyl) optionally substituted with C _1-4 alkyl;
-C _0-4 alkyl-pyrrolyl (eg 1-methylpyrrolidin-2-ylmethyl) optionally substituted with -C _0-4 alkyl;
Para-phenylbenzyl;
(iv) R ₁ is H or C _1-4 alkyl (eg methyl);
(v) R ₂ is selected from the group consisting of H, C _1-4 alkyl (eg methyl) and —OC _3-8 cycloalkyl ¹ (eg —O-cyclopentyl);
(vi) R ₆ is H or C _1-4 alkyl (eg methyl);
(vii) R ₁₁ and R ₁₂ are independently H or C _1-4 alkyl (eg methyl)} or
i) The compound according to any one of claims 8-18. The method of claim 19, wherein the infection is a gram positive or gram negative bacterial infection. 21. The method of claim 19 or 20, wherein the bacterial infection is Clostridium difficile ), Moraxella catarrhalis ), Klebsiella pneumoniae , Staphylococcus epidermidis , Streptococcus viridans , Enterococcus faecium , Staphylococcus faecium , Staphylococcus faecium Staphylococcus aureus , Bacillus anthracis , Francisella tularensis Streptococcus pneumoniae, Pseudomonas aeruginosa , Acinetobacter Baumann Acinetobacter baumannii , Brucella melitensis , Escherichia coli , Haemophilus influenzae , Listeria monocytogenes , Salmonella enterica ), in V. cholera (Vibrio cholerae), Enterococcus faecalis nose kusu par (Enterococcus faecalis), Hyeres shinny The method of pestiviruses switch (Yersinia pestis), Bacillus subtilis (Bacillus subtilis), streptococcus blood comes Ness (Streptococcus pyogenes), and ah borelri Hamburg D'Perry selected from the group consisting of (Borrelia burgdorferi). 22. The method of any one of claims 19-21, wherein the bacterial infection is Clostridium difficile infection. 22. The method of any one of claims 19-21, wherein said bacterial infection is a Staphylococcus aureus infection. 24. The method of any one of claims 19-23, wherein the infection is by an infectious agent that is resistant to a drug that is not a riboswitch ligand. The method of claim 19, wherein the infection is resistant to one or more drugs selected from the group consisting of penicillin, vancomycin, cephalosporin and methicillin. The method of claim 25, wherein the infection is methicillin-resistant Staphylococcus aureus infection. The seed of claim 19, wherein the infection is fluoroquinolone-resistant (eg, ciprofloxacin- and / or levofloxacin-resistant), metronidazole, and / or vancomycin-resistant seed. C. difficile infection. The method of any one of claims 19-27, wherein the compound is a compound of Formula Q in free or pharmaceutically acceptable salt form. 28. The compound of any one of claims 19-27, wherein the compound is in free or pharmaceutically acceptable salt form. 29. Q.35, Q.36, Q.37, Q.38, Q.39, Q. And from the group consisting of compounds described as any of 40 or Q.41. 28. The method of any one of claims 19-27, wherein said compound is selected from the group consisting of compounds described in Formula Q.41 in free or pharmaceutically acceptable salt form. 28. The method of any one of claims 19-27, wherein the compound is a compound of Formula II in free or pharmaceutically acceptable salt form. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 in free or pharmaceutically acceptable salt form mixed with a pharmaceutically acceptable diluent or carrier. Use of a compound according to claim 19 or a pharmaceutical composition according to claim 32 in the manufacture of a medicament for the treatment or prevention of a bacterial infection. The method of claim 33, wherein the infection is Clostridium difficile, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus paesium, Staphylococcus aureus, Bacillus anthracis, Francisella tullarensis, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannini, Brusella mellitosis, Eshericia coli, Hae Mophilus influenzae, Listeria monocytogenes, Salmonella enterica, Vibrio cholera, Enterococcus paecalis, Yersinian pestis, Bacillus subtilis, Streptococcus piogenes and Borelia burgdorfferin bacteria Use that is an infection caused by one or more of them. Anthrax, Staphylococcal tear skin syndrome (Staphylococcal infection), pneumonia, impetigo, boils, cellulitis, folliculitis, furuncle, carbuncle, laceration skin syndrome, abscess, meningitis, Osteomyelitis, endocarditis, toxic shock syndrome (TSS), sepsis, acute sinusitis, otitis media, infectious arthritis, endocarditis, peritonitis, peritonitis, cellulitis, brain abscess, yatopathy, urinary tract infection, livestock, food poisoning, diarrhea, conjunctivitis and Clostridium diffi Use of a compound according to claim 19 or a pharmaceutical composition according to claim 32 in the manufacture of a medicament for the treatment of a disease, condition or infection selected from the group consisting of room related diseases (CDAD). A method for the treatment or prevention of a bacterial infection in a plant, comprising administering to the plant an effective amount of the compound according to claim 19 in free or pharmaceutically acceptable salt form.